Cell differentiation inducer

ABSTRACT

The novel benzamide derivative represented by formula (1) and the novel anilide derivative represented by formula (13) of this invention has differentiation-inducing effect, and are, therefore, useful a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as an anticancer drug, specifically to a hematologic malignancy and a solid carcinoma.

This application is a divisional, of application Ser. No. 08/935,087,filed Sep. 26, 1997 now U.S. Pat. No. 6,174,905.

FIELD OF THE INVENTION

This invention relates to a differentiation-inducing agent. Inparticular, this invention relates to the use of a novel benzamidederivative or anilide derivative for an anticancer drug or other drugsbased on its differentiation-inducing activity.

DESCRIPTION OF THE RELATED ART

Cancers have now become a top cause of death, exceeding heart andcerebrovascular diseases, and so many studies have been conducted withenormous expense and time to overcome cancers. They have not been,however, overcome in spite of a variety of investigations for therapysuch as a surgical operation, a radiation therapy and thermotherapy.Among those therapies, chemotherapy is one of the main area for cancertreatment. To date, however, no satisfactory drugs have been discovered,and thus an anticancer drug with reduced toxicity and high therapeuticeffect has been desired. Many of the conventional anticancer drugs showtheir effect by affecting mainly DNA to express their cytotoxicity andthen injuring carcinoma cells. However, since they do not havesufficient selectivity between carcinoma cells and normal cells, adversereactions expressed in normal cells have limited their use in therapy.

Meanwhile, differentiation-inducing agents among anticancer drugs areintended to induce differentiation of carcinoma cells for controllingtheir infinite proliferation, rather than directly kill the cells.

The agents may, therefore, be inferior to the anticancer drugs directlykilling carcinoma cells, with regard to involution of a carcinoma, butmay be expected to have reduced toxicity and different selectivity. Infact, it is well known that retinoic acid, a differentiation-inducingagent, may be used for treatment of acute promyelogenous leukemia toexhibit a higher effect [Huang et al., Blood, 72, 567-572(1988);Castaign et al., Blood, 76, 1704-1709 (1990); Warrell et al., New Engl.J. Med. 324, 1385-1393(1991) etc.]. In addition, vitamin D derivativesexhibit differentiation-inducing effect, and thus their application foranticancer drugs have been investigated [e.g., Olsson et al, Cancer Res.43, 5862-5867(1983) etc.].

As the results of these investigations, there have been reportedapplications for anticancer drugs, of a variety ofdifferentiation-inducing agents such as vitamin D derivatives (JP-A6-179622), isoprene derivatives (JP-A 6-192073), tocopherol (JP-A6-256181), quinone derivatives (JP-A 6-305955), noncyclicpolyisoprenoids (JP-A 6-316520), benzoic acid derivatives (JP-A7-206765) and glycolipids (JP-A 7-258100). There have been no agentshaving sufficient level of effect for cancer treatment in spite of theinvestigations, and thus there has been greatly desired a highly safeagent effective to a variety of cancers.

SUMMARY OF THE INVENTION

An objective of this invention is to provide a compound which exhibitsdifferentiation-inducing effect and is useful as a pharmaceutical agentsuch as therapeutic or improving agents for malignant tumors, autoimmunediseases, dermatologic diseases and parasitism.

We have intensely attempted to achieve the above objective and havefound that a novel benzamide derivative and a novel anilide derivativehaving differentiation-inducing effect show antitumor effect, leading tothis invention. Specifically, this invention provides a compoundrepresented by formula (1) or a pharmaceutically acceptable saltthereof,

wherein A is an optionally substituted a phenyl or heterocyclic groupwhich has 1 to 4 substituents selected from the group consisting of ahalogen atom, a hydroxyl group, an amino group, a nitro group, a cyanogroup, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylaminogroup having 1 to 4 carbons, an acyl group having 1 to 4 carbons, anacylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4carbons, a perfluoroalkyl group having 1 to 4 carbons, aperfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group, analkoxycarbonyl group having 1 to 4 carbons, a phenyl group and aheterocyclic group;

X is a bond or a moiety having a structure selected from thoseillustrated in formula (2)

wherein e is an integer of 1 to 4; g and m are independently an integerof 0 to 4; R⁴ is hydrogen or an optionally substituted alkyl grouphaving 1 to 4 carbons, or the acyl group represented by formula (3)

wherein R⁶ is an optionally substituted alkyl group having 1 to 4carbons, a perfluoroalkyl group having 1 to 4 carbons, a phenyl group ora heterocyclic group; R⁵ is hydrogen or an optionally substituted alkylgroup having 1 to 4 carbons;

n is an integer of 0 to 4, provided that when X is a bond, n is notzero;

Q is a moiety having a structure selected from those illustrated informula (4)

wherein R⁷ and R⁸ are independently hydrogen or an optionallysubstituted alkyl having 1 to 4 carbons;

R¹ and R² are independently a hydrogen atom, a halogen atom, a hydroxylgroup, amino group, an alkyl group having 1 to 4 carbons, an alkoxygroup having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons,an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4carbons, an acylamino group having 1 to 4 carbons, an alkylthio grouphaving 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, aperfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group or analkoxycarbonyl group having 1 to 4 carbons;

R³ is a hydroxyl or amino group.

This invention also provides an anilide having the structure representedby formula (13)

wherein A and R³ are as defined above; B is an optionally substituted aphenyl or heterocycle group; Y is a moiety having —CO—, —CS—, —SO— or—SO₂— which is linear, cyclic or their combination and links A and B;and in which the distances between the centroid of ring B (W1), thecentroid of ring A (W2) and an oxygen or sulfur atom as a hydrogen bondacceptor in the moiety Y (W3) can be as follows; W1-W2=6.0 to 11.0 Å,W1-W3=3.0 to 8.0 Å, and W2-W3=3.0 to 8.0 Å; preferably W1-W2=7.0 to 9.5Å; W1-W3 is 3.0 to 5.0 Å; and W2-W3 is 5.0-8.0 Å; or a pharmaceuticallyacceptable salt thereof.

The novel benzamide derivative and the novel anilide derivative of thisinvention have differentiation-inducing effect and are useful as a drugsuch as a therapeutic or improving agent for malignant tumors,autoimmune diseases, dermatologic diseases and parasitism. Inparticular, they are highly effective as a carcinostatic agent,specifically to a hematologic malignancy and a solid carcinoma.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a change of the volume of the tumor when the compound ofExample 48 was administered against the tumor cell HT-29.

FIG. 2 shows a change of the volume of the tumor when the compound ofExample 48 was administered against the tumor cell KB-3-1.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In the above formula (1), n may be zero or an integer of 1 to 4.

Q in the above formula (1) may be any structure illustrated in formula(5);

wherein R⁷ and R⁸ are as defined above.

X in the above formula (1) may be a moiety having the structurerepresented by formula (6);

—(CH₂)e-   (6)

wherein e is as defined above.

X in the above formula (1) may be also a moiety having any structureillustrated in formula (7);

wherein e, g and R⁴ areas defined above.

X in the above formula (1) may be also a moiety having any structureillustrated in formula (8);

wherein g, m and R⁵ are as defined above.

The anilide represented by formula (13) may be one wherein A is anoptionally substituted heterocycle; B is an optionally substitutedphenyl; and R³ is an amino group.

The anilide may be also one wherein Y has —CO— and is linear, cyclic ortheir combination.

As used herein, “1 to 4 carbons” means a carbon number per a singlesubstituent; for example, for dialkyl substitution it means 2 to 8carbons.

A heterocycle in the compound represented by formula (1) or (13) is amonocyclic heterocycle having 5 or 6 members containing 1 to 4 nitrogen,oxygen or sulfur atoms or a bicyclic-fused heterocycle. The monocyclicheterocycle includes pyridine, pyrazine, pyrimidine, pyridazine,thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole,oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine,tetrahydrofuran, morpholine, thiomorpholine and the like. The bicyclicfused heterocycle includes. quinoline; isoquinoline; naphthyridine;fused pyridines such as furopyridine, thienopyridine, pyrrolopyridine,oxazolopyridine, imidazolopyridine and thiazolopyridine; benzofuran;benzothiophene; benzimidazole and the like.

A halogen may be fluorine, chlorine, bromine or iodine.

An alkyl having 1 to 4 carbons includes methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

An alkoxy having 1 to 4 carbons includes methoxy, ethoxy, n-propoxy,isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy andthe like.

An aminoalkyl having 1 to 4 carbons includes aminomethyl, 1-aminoethyl,2-aminopropyl and the like.

An alkylamino having 1 to 4 carbons includes N-methylamino,N,N-dimethylamino, N,N-diethylamino, N-methyl-N-ethylamino,N,N-diisopropylamino and the like.

An acyl having 1 to 4 carbons includes acetyl, propanoyl, butanoyl andlike.

An acylamino having 1 to 4 carbons includes acetylamino, propanoylamino,butanoylamino and the like.

An alkylthio having 1 to 4 carbons includes methylthio, ethylthio,propylthio and the like.

A perfluoroalkyl having 1 to 4 carbons includes trifluoromethyl,pentafluoroethyl and the like.

A perfluoroalkyloxy having 1 to 4 carbons includes trifluoromethoxy,pentafluoroethoxy and the like.

An alkoxycarbonyl having 1 to 4 carbons includes methoxycarbonyl andethoxycarbonyl.

An optionally substituted alkyl having 1 to 4 carbons includes methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyland these having 1 to 4 substituents selected from the group consistingof a halogen, hydroxyl, amino, nitro, cyano, phenyl and a heterocycle.

As described below, important elements in the compound represented byformula (13) are (a) presence of ring A, ring B and oxygen or sulfuratom as a hydrogen bond acceptor, and (b) the distances between themdetermined by their steric configurations. There may be, therefore, nolimitation as long as the structure of Y has a hydrogen bond accptor andrings A and B have required steric configurations. Specifically, thestructure of Y which has —CO—, —CS—, —SO— or —SO₂— and links A and B andwhich is linear, cyclic or their combination, means either (a) oneconsisting of carbon and/or hetero atoms linking A and B, whose linearor branched moiety has —CO—, —CS—, —SO— or —SO₂—; (b) one linking A andB, whose cyclic moiety has —CO—, —CS—, —SO— or —SO₂—; and (c) onelinking A and B where in a combination of cyclic and linear moietiesform a structural unit having —CO—, —CS—, —SO— or —SO₂—.

A basic cyclic structure includes cyclic moieties having 4 to 7 memberscontaining carbons and/or hetero atoms or their fused cycles. Forexample it may be cyclobutane, cyclopentane, cyclohexane, cycloheptane,oxetane, oxolane, oxane, oxepane, pyrrolidine, imidazolidine,pyrazolidine, piperidine, piperazine, indoline, isoindoline, thiolane,thiazolidine and oxazolidine rings, which may contain unsaturated bonds,hydrogen bond acceptors and/or substituents.

Structural analyses considering degree of conformational freedom of thecompound represented by formula (13) have indicated that atomic groupspossibly involved in an biomolecule-drug interaction such as ahydrophobic interaction and hydrogen bond may have a particular spatialconfiguration in a compound showing high differentiation-inducingeffect.

Specifically, we formed a three-dimensional structure of a high activitycompound using a molecular modeling software, SYBYL 6.3, and analyzedconformations for all rotatable bonds to determine the most stablestructure, wherein their energy levels were evaluated by using Triposforce field after allocating charge on each atom according toGasteiger-Huckel method. Then, starting with the most stable structure,we have performed a superimposition taking its conformation intoconsideration using DISCO/SYBYL and then have found that a particularspatial configuration is necessary for expression of highdifferentiation-inducing effect.

In the above analyses, other commercially available program packagessuch as CATALYST(MSI), Cerius 2/QSAR+(MSI) and SYBYL/DISCO(Tripos) maybe used, and the information on distance obtained in this invention isnot limited to that from a particular calculation program.

The ring centroid used in definition of the spatial configuration may bedefined as an average of X, Y and Z axes of the ring-forming atoms. Whena ring structure to be calculated is fused-polycyclic, the centroid ofeither the overall fused ring or of a partial ring may be used as thatfor defining the space.

“Possibility of formation of a configuration” means that a conformerfilling the spatial configuration is within 15 kcal/mol, preferably 8kcal/mol from the energetically most stable structure.

Specific calculation can be performed as described in the instructionsfor Sybyl (M. Clark) or J. Comput. Chem. 10, 982(1989).

A pharmaceutically acceptable salt of the compound of this inventionincludes salts with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid and phosphoric acid; and with an organicacid such as acetic acid, lactic acid, tartaric acid, malic acid,succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid,trifluroacetic acid, p-toluenesulfonic acid and methanesulfonic acid.Such a salt includesN-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidehydrochloride,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidehydrobromide,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidesulfate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidephosphate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamideacetate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidelactate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl)benzamidetartrate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidemalate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidesuccinate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidefumarate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidemaleate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidecitrate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidetrifluoroacetate,N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidep-toluenesulfonate andN-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamidemethanesulfonate.

As used herein, a “drug” includes a therapeutic and/or improving agentto, for example, an autoimmune disease, dermatologic disease orparasitism, in addition to a anticancer drug.

When having asymmetric carbon or carbons, the compound represented byformula (1) or (13) may be obtained as an individual stereoisomer or amixture of stereoisomers including a racemic modification. Thisinvention encompasses the above-specified different forms, which may bealso used as an active ingredient.

Representative compounds of this invention represented by formula (1) or(13) are specifically shown in Tables 1 to 4, but this invention is notintended to be limited to these.

TABLE 1

Compound No. A X Q n R1 R2 R3 1

Direct bond

1 H H NH₂ 2

—CH₂—

0 H H NH₂ 3

—(CH₂)₂—

0 H H NH₂ 4

—(CH₂)₃—

0 H H NH₂ 5

—(CH₂)₄—

0 H H NH₂ 6

—CH₂—

1 H H NH₂ 7

—(CH₂)₂—

1 H H NH₂ 8

—CH₂—

0 H H NH₂ 9

—(CH₂)₂—

0 H H NH₂ 10

Direct bond

1 H H NH₂ 11

—CH₂—

1 H H NH₂ 12

Direct bond

1 H H NH₂ 13

Direct bond

1 H H NH₂ 14

Direct bond

1 H H NH₂ 15

—CH₂—

0 H H NH₂ 16

Direct bond

1 H H NH₂ 17

Direct bond

1 H H NH₂ 18

Direct bond

1 H H NH₂ 19

—CH₂—

0 H H NH₂ 20

Direct bond

1 H H NH₂ 21

—CH₂—

0 H H NH₂ 22

—CH₂—

0 H H NH₂ 23

—CH₂—

1 H H NH₂ 24

Direct bond

1 H H NH₂ 25

Direct bond

1 H H NH₂ 26

—CH₂—

0 H H NH₂ 27

Direct bond

1 H H NH₂ 28

Direct bond

1 H H NH₂ 29

Direct bond

1 H H NH₂ 30

Direct bond

1 H H NH₂ 31

Direct bond

1 H H NH₂ 32

—CH₂—

0 H H NH₂ 33

Direct bond

1 H H NH₂ 34

—CH₂—

1 H H NH₂ 35

Direct bond

1 H H NH₂ 36

Direct bond

1 H H NH₂ 37

Direct bond

1 H H NH₂ 38

—CH₂—

1 H H NH₂ 39

—CH₂—

1 H H NH₂ 40

Direct bond

1 H H NH₂ 41

Direct bond

1 H H NH₂ 42

Direct bond

1 H H NH₂ 43

—CH₂—

0 H H NH₂ 44

Direct bond

1 H H NH₂ 45

Direct bond

1 H H NH₂ 46

Direct bond

1 H H NH₂ 47

—CH₂—

1 H H NH₂ 48

—O—CH₂—

1 H H NH₂ 49

—S—CH₂—

1 H H NH₂ 50

1 H H NH₂ 51

—CH₂—

1 H H NH₂ 52

—CH₂—

1 H H NH₂ 53

—CH₂—

0 H H NH₂ 54

—O—CH₂—

0 H H NH₂ 55

—O—CH₂—

0 H H NH₂ 56

—O—CH₂—

1 H H NH₂ 57

—O—CH₂—

1 H 5-F NH₂ 58

—CH₂—O—CH₂—

0 H H NH₂ 59

1 H H NH₂ 60

1 H H NH₂ 61

—O—CH₂—

1 H H NH₂ 62

—O—(CH₂)₂—

1 H H NH₂ 63

1 H H NH₂ 64

—S—CH₂—

1 H H NH₂ 65

—O—CH₂—

0 H H NH₂ 66

—O—(CH₂)₂—

0 H H NH₂ 67

—O—(CH₂)₂—

0 H H NH₂ 68

—CH₂—

0 H H NH₂ 69

—(CH₂)₂—

0 H H NH₂ 70

—(CH₂)₂—

0 H H NH₂ 71

Direct bond

1 H H NH₂ 72

Direct bond

2 H H NH₂ 73

Direct bond

3 H H NH₂ 74

—CH₂—

1 H H NH₂ 75

—(CH₂)₂—

1 H H NH₂ 76

—(CH₂)₃—

1 H H NH₂ 77

—CH₂—

2 H H NH₂ 78

—CH₂—

1 H H NH₂ 79

Direct bond

2 H H NH₂ 80

—CH₂—

2 H H NH₂ 81

Direct bond

1 H H NH₂ 82

—CH₂—

1 H H NH₂ 83

—(CH₂)₂—

1 H H NH₂ 84

—(CH₂)₃—

1 H H NH₂ 85

—CH₂—

1 H H NH₂ 86

—CH₂—

1 H H NH₂ 87

Direct bond

1 H H NH₂ 88

—CH₂—

1 H H NH₂ 89

—(CH₂)₂)—

1 H H NH₂ 90

—CH₂—

1 H H NH₂ 91

—O—CH₂—

1 H H NH₂ 92

—O—CH₂—

1 H H NH₂ 93

—O—CH₂—

1 H H OH 94

0 H H NH₂ 95

1 H H NH₂ 96

1 H H NH₂ 97

0 H H NH₂ 98

1 H H NH₂ 99

0 H H NH₂ 100

1 H H NH₂ 101

—CH₂—O—CH₂—

0 H H NH₂ 102

—CH₂—O—CH₂—

0 3-CH₃ H NH₂ 103

—CH₂—O—CH₂—

0 H H NH₂ 104

0 H H NH₂ 105

0 H H NH₂ 106

0 H H NH₂ 107

1 H H NH₂ 108

0 H H NH₂ 109

—CH₂—

1 H H NH₂ 110

—CH₂—

1 H 5-F NH₂ 111

—CH₂—

1 H H OH 112

—CH₂—

1 H 5-F NH₂ 113

—CH₂—

1 H 4-Cl NH₂ 114

—CH₂—

1 H H OH 115

—CH₂—

1 H H OH 116

—CH₂—

1 H 4-OH OH 117

—CH₂—

1 H H OH 118

—CH₂—

1 H 5-CH₃ OH 119

—CH₂—

1 H 5-OCH₃ OH 120

—CH₂—

1 H H NH₂ 121

—CH₂—

1 H 5-OCH₃ NH₂ 122

—(CH₂)₂—

0 H 5-F NH₂ 123

—(CH₂)₂—

0 3-Cl H NH₂ 124

—(CH₂)₂—

0 H H NH₂ 125

—(CH₂)₂—

1 H H OH 126

1 H H NH₂ 127

1 H H NH₂ 128

—O—CH₂—

1 2-Cl H NH₂ 129

—O—CH₂—

1 H 5-F NH₂ 130

—O—CH₂—

1 H 5-OCH₃ NH₂ 131

—CH₂—

1 H H NH₂ 132

—O—CH₂—

1 H H NH₂ 133

—CH₂—O—CH₂—

1 H H NH₂ 134

—CH₂—

1 H H NH₂ 135

—O—CH₂—

1 H H NH₂ 136

—CH₂—O—CH₂—

1 H H NH₂ 137

—CH₂—

1 H H NH₂ 138

—O—CH₂—

1 H H NH₂ 139

—CH₂—O—CH₂—

1 H H NH₂ 140

—CH₂—

1 H 5-F NH₂ 141

Direct bond

1 H H NH₂ 142

—CH₂—

1 H H NH₂ 143

Direct bond

1 H H NH₂ 144

—CH₂—

1 H H NH₂ 145

—CH₂—

1 H H NH₂ 146

—CH₂—

1 H H NH₂ 147

—CH₂—

1 H H NH₂ 148

—CH₂—

1 H H NH₂ 149

—CH₂—

1 H H NH₂ 150

—(CH₂)₂—

1 H H NH₂ 151

—(CH₂)₂—

1 H H NH₂ 152

—(CH₂)₂—

0 H H NH₂ 153

—CH₂—

2 H H NH₂ 154

Direct bond

1 H H NH₂ 155

—CH₂—

1 H H NH₂ 156

Direct bond

1 H H NH₂ 157

—CH₂—

1 H H NH₂ 158

—O—CH₂—

1 H H NH₂ 159

—O—CH₂—

1 H H NH₂ 160

—CH₂—

1 H H NH₂ 161

—CH₂—

1 H H NH₂ 162

—CH₂—

1 H H NH₂ 163

—CH₂—

1 H H NH₂ 164

—(CH₂)₂—

1 H H NH₂ 165

—(CH₂)₂—

1 H H NH₂ 166

—(CH₂)₂—

0 H H NH₂ 167

—CH₂—

2 H H NH₂ 168

—CH₂—

1 H H NH₂ 169

—CH₂—

1 H H NH₂ 170

—CH₂—

1 H H NH₂ 171

—CH₂—

1 H H NH₂ 172

—(CH₂)₂—

1 H H NH₂ 173

Direct bond

1 H H NH₂ 174

—CH₂—

0 H H NH₂ 175

—O—CH₂—

1 H 5-OCH₃ NH₂ 176

—CH₂—O—CH₂—

0 H H NH₂ 177

—CH₂—

0 H H NH₂ 178

Direct bond

1 H H NH₂ 179

—CH₂—

1 H H NH₂ 180

—CH₂—

1 H H NH₂ 181

—CH₂—

1 H H NH₂ 182

—(CH₂)₂—

1 H H NH₂ 183

Direct bond

1 H H NH₂ 184

—CH₂—

0 H H NH₂ 185

—CH₂—

0 H H NH₂ 186

—CH₂—

1 H H NH₂ 187

—CH₂—

0 H H NH₂ 188

Direct bond

1 H H NH₂ 189

—CH₂—

1 H H NH₂ 190

—CH₂—

1 H H NH₂ 191

Direct bond

1 H H NH₂ 192

—CH₂—

1 H H NH₂ 193

—CH₂—O—CH₂—

1 H H NH₂ 194

—CH₂—O—CH₂—

0 H H NH₂ 195

Direct bond

1 H H NH₂ 196

—CH₂—

1 H H NH₂ 197

Direct bond

1 H H NH₂ 198

—CH₂—

1 H H NH₂ 199

—CH₂—O—CH₂—

1 H H NH₂ 200

—CH₂—O—CH₂—

0 H H NH₂ 201

Direct bond

1 H H NH₂ 202

—CH₂—

1 H H NH₂ 203

—(CH₂)₂—

1 H H NH₂ 204

—CH₂—O—CH₂—

0 H H NH₂ 205

Direct bond

1 H H NH₂ 206

—CH₂—

1 H H NH₂ 207

—CH₂—O—CH₂—

1 H H NH₂ 208

—CH₂—O—CH₂—

0 H H NH₂ 209

Direct bond

1 H H NH₂ 210

Direct bond

1 H H NH₂ 211

—CH₂—

1 H H NH₂ 212

Direct bond

1 H H NH₂ 213

Direct bond

1 H H NH₂ 214

Direct bond

1 H H NH₂ 215

—(CH₂)₃—

1 H H NH₂ 216

—CH₂—

1 H H NH₂ 217

—(CH₂)₂—

1 H H NH₂ 218

—CH₂—

1 H H NH₂ 219

—CH₂—

1 H H NH₂ 220

—CH₂—

1 H H NH₂ 221

—CH₂—

1 H H NH₂ 222

—CH₂—O—CH₂—

1 H H NH₂ 223

—CH₂—O—CH₂—

1 H H NH₂ 224

Direct bond

1 H H NH₂ 225

—CH₂—

1 H H NH₂ 226

—CH₂—O—CH₂—

1 H H NH₂ 227

—(CH₂)₃—

1 H H NH₂ 228

Direct bond

1 H H NH₂ 229

—CH₂—

1 H H NH₂ 230

CH₂—O—CH₂—

1 H H NH₂ 231

Direct bond

1 H H NH₂ 232

Direct bond

1 H H NH₂ 233

Direct bond

1 H H NH₂ 234

Direct bond

1 H H NH₂ 235

Direct bond

1 H H NH₂ 236

Direct bond

1 H H NH₂ 237

Direct bond

1 H H NH₂ 238

Direct bond

1 H H NH₂ 239

Direct bond

1 H H NH₂ 240

Direct bond

1 H H NH₂

TABLE 2 Compound No. Structural formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

TABLE 3 Compound No. Structural formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 4 Compound No. Structural formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

The compound of this invention may be prepared as described below.

(a) A compound represented by formula (14);

—A—X—R⁹  (14)

wherein A and X are as defined above; R⁹ is —C(═G)OH (G is an oxygen orsulfur atom) or —NH₂;

is condensed with a compound represented by formula (15);

wherein R¹, R² and n are as defined above; R¹⁰ is —NH₂ when R⁹ is—C(═G)OH (G is as defined above) and —C(═G)OH (G is as defined above)when R⁹ is —NH₂; R¹¹ is an amino group protected with a protective groupused in a common peptide-forming reaction, e.g., tert-butoxycarbonyl ora hydroxyl group protected with a protecting group commonly used in apeptide-forming reaction, including benzyl.

(b) A compound represented by formula (16)

A—X—R¹²  (16)

wherein A and X are as defined above; and R¹² is —OH or —NH₂;

is condensed with a compound represented by formula (17);

wherein R¹, R², R¹¹ and n are as defined above; R¹³ is —OH or —NH₂;

using an agent such as N,N′-carbonyldiimidazole,N,N′-thiocarbonyldiimidazole, phosgene or thiophosgene, to give acompound represented by formula (18);

wherein A, X, Q, n, R¹, R² and R¹¹ are as defined above, whoseprotecting group is then removed to give the compound of this invention.

(c) A compound represented by formula (14) is condensed with a compoundrepresented by formula (19);

wherein R¹, R¹⁰ and n are as defined above; R¹⁴ is a methyl, ethyl ortert-butyl group.

(d) A compound represented by formula (16) is condensed with a compoundrepresented by formula (20);

wherein R¹, R¹³, R¹⁴ and n are as defined above; using an agent such asN,N′-carbonyldiimidazole, N,N′-thiocarbonyldiimidazole, phosgene orthiophosgene to give a compound represented by formula (21);

wherein A, X, Q, n, R¹ and R¹⁴ are as defined above; which is thenhydrolyzed to give a compound represented by formula (22);

wherein A, X, Q, n and R¹ are as defined above. The product is condensedwith a compound represented by formula (23);

wherein R² and R¹¹ are as defined above; to give a compound representedby formula (18) whose protecting group is then removed to give thecompound of this invention.

(e) A compound represented with formula (22) is condensed with acompound represented by formula (24);

wherein R² and R³ are as defined above; to give the compound of thisinvention.

Preparation procedures for typical intermediates are shown below.

A compound represented by formula (15) may be prepared by introducing anappropriate protecting group to a benzoic acid derivative represented byformula (25);

wherein R¹, R¹⁰ and n are as defined above; condensing the product witha compound represented by formula (23), and removing the protectinggroup of the condensation product.

A compound represented by formula (17) may be prepared by introducing anappropriate protecting group to a benzoic acid derivative represented byformula (26);

wherein R¹, R¹³ and n are as defined above; condensing the product witha compound represented by formula (23), and removing the protectinggroup of the condensation product.

A compound represented by formula (23) may be prepared by introducing aprotecting group to a compound represented by formula (24).

Next, reactions used for preparation of the compound of this inventionwill be described.

The condensation reaction in (a) may be an amide-bond forming reactionfor a usual peptide using, for example, an activated ester, a mixed acidanhydride or an acid halide. For example, a carboxylic acid, i.e., acompound represented by formula (14) wherein R⁹ is —C(═G)OH (G is asdefined above) or a compound represented by formula (15) wherein R¹⁰ is—C(═G)OH (G is as defined above), may be condensed with a phenolderivative such as 2,4,5-trichlorophenol, pentachlorophenol and4-nitrophenol, or an N-hydroxy compound such as N-hydoxysuccinimide andN-hydroxybenzotriazole, in the presence of dicyclohexylcarbodiimide, tobe converted into an activated ester, which is then condensed with anamine represented by formula (14) wherein R⁹ is —NH₂ or by formula (15)wherein R¹⁰ is —NH₂, to give the desired product.

Alternatively, a carboxylic acid represented by formula (14) wherein R⁹is —C(═G)OH (G is as defined above) or by formula (15) wherein R¹⁰ is—C(═G)OH (G is as defined above), may be reacted with, for example,oxalyl chloride, thionyl chloride or phosphorus oxychloride to beconverted into an acid chloride, which is then condensed with an aminerepresented by formula (14) wherein R⁹ is —NH₂ or by formula (15)wherein R¹⁰ is —NH₂, to give the desired product.

Furthermore, a carboxylic acid represented by formula (14) wherein R⁹ is—C(═G)OH (G is as defined above) or by formula (15) wherein R¹⁰ is—C(═G)OH (G is as defined above), may be reacted with, for example,isobutyl chlorocarbonate or methanesulfonyl chloride to be convertedinto a mixed acid anhydride, which is then condensed with an aminerepresented by formula (14) wherein R⁹ is —NH₂ or by formula (15)wherein R¹⁰ is —NH₂, to give the desired product.

The above condensation reaction may be conducted solely using a peptidecondensing agent such as dicyclohexylcarbodiimide,N,N′-carbonyldiimidazole, diphenyl phosphoric azide,diethylphosphorylcyanide, 2-chloro-1,3-dimethylimidazolonium chloride,etc.

The reaction may be usually conducted at −20 to +50° C. for 0.5 to 48hours. Solvents which may be used include aromatic hydrocarbons such asbenzene, toluene and the like; ethers such as tetrahydrofuran, dioxane,diethyl ether and the like; halogenated hydrocarbons such asdichloromethane, chloroform and the like; N,N-dimethylformamide;alcohols such as methanol, ethanol and the like; and a mixture thereof.If necessary, an organic base such as triethylamine and pyridine may beadded.

The condensation reaction in (b) may be conducted by activating acompound represented by either formula (16) or (17) with, for example,phosgene, thiophosgene, N,N′-carbonyldiimidazole,N,N′-thiocarbonyldiimidazole or the like and then reacting the activatedproduct with the other compound. The reaction may be usually conductedat −20 to +50° C. for 0.5 to 48 hours. Solvents which may be usedinclude aromatic hydrocarbons such as benzene, toluene and the like;ethers such as tetrahydrofuran, dioxane, diethyl ether and the like;halogenated hydrocarbons such as dichloromethane, chloroform and thelike; N,N-dimethylformamide; and a mixture thereof. If necessary, anorganic base such as triethylamine, pyridine and the like may be added.

The condensation reaction in (c) maybe conducted as the condensation in(a).

The condensation reaction in (d) may be conducted as the condensation in(b).

The protecting group of the compound represented by formula (17) may beremoved under the conditions used in a common peptide-forming reaction.For example, when R¹¹ in formula (18) is the amino group protected withtert-butoxycarbonyl, it may be deprotected by treatment with an acidsuch as hydrochloric acid, trifluoroacetic acid or the like.

A salt of a compound represented by formula (1) or (13) maybe formedduring preparation of the compound, but is usually formed by treatingthe compound with a pharmaceutically acceptable acid. Such an acidincludes inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid and the like; and organic acids such asacetic acid, tartaric acid, fumaric acid, maleic acid, citric acid,benzoic acid, trifluroacetic acid, p-toluenesulfonic acid and the like.These salts may be also used as an active ingredient in this invention,as the free base, the compound represented by formula (1) or (13).

A compound represented by formula (1) or (13) may be purified orisolated by a usual separation method such as extraction,recrystallization, column chromatography and the like.

The novel benzamide or anilide derivative of this invention hasdifferentiation-inducing effect and thus is useful as a therapeuticand/or improving agent to a variety of diseases such as malignanttumors, autoimmune diseases, dermatologic diseases and parasitism.

As used herein, a “malignant tumor” includes hematologic malignancy suchas acute leukemia, malignant lymphoma, multiple myeloma andmacroglobulinemia as well as solid tumors such as colon cancer, cerebraltumor, head and neck tumor, breast carcinoma, pulmonary cancer,esophageal cancer, gastric cancer, hepatic cancer, gallbladder cancer,bile duct cancer, pancreatic cancer, nesidioblastoma, renal cellcarcinoma, adrenocortical cancer, urinary bladder carcinoma, prostaticcancer, testicular tumor, ovarian carcinoma, uterine cancer, chorioniccarcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer,malignant melanoma, osteogenic sarcoma, soft tissue sarcoma,neuroblastoma, Wilms tumor and retinoblastoma.

An autoimmune disease includes rheumatism, diabetes, systemic lupuserythematodes, human autoimmune lymphocytotic lymphadenopathy,immunoblastic lymphadenopathy, Crohn disease and ulcerative colitis.

A dermatologic disease includes psoriasis, acne, eczema and atopicdermatitis.

Parasitism includes diseases such as malaria caused through vermination.

Indications for the compound of this invention are not limited to thesespecific examples.

The active ingredient of this invention useful as a drug may be used inthe form of a general pharmaceutical composition. The pharmaceuticalcomposition may be prepared with generally used diluents or excipientssuch as filler, extender, binder, moisturizing agent, disintegrator,surfactant and lubricant. The pharmaceutical composition may have avariety of dosage forms depending on its therapeutic purpose; typicallytablet, pill, powder, solution, suspension, emulsion, granule, capsule,injection (e.g., solution, suspension) and suppository.

For preparing tablets, a variety of carriers well-known in the art maybe used. Such a carrier includes excipients such as lactose, glucose,starch, calcium carbonate, kaoline, crystalline cellulose and silicicacid; binders such as water, ethanol, propanol, simple syrup, glucosesolution, starch solution, gelatin solution, carboxymethyl cellulose,shellac, methyl cellulose and polyvinyl pyrrolidone; disintegrators suchas dried starch, sodium alginate, powdered agar, calcium carmelose,starch and lactose; disintegration retarders such as sucrose, cocoabutter and hydrogenated oil; absorption promoters such as quaternaryammonium base and sodium lauryl sulfate; moisturizing agents such asglycerin and starch; adsorbents such as starch, lactose, kaoline,bentonite, colloidal silicic acid; and glidants such as talc, stearatesand polyethylene glycol. The tablet may be, if necessary, one coatedwith a common coating; for example, sugar-coated tablet, gelatin-coatedtablet, enteric coated tablet, film-coated tablet, double-layer tabletand multilayer tablet.

In forming pills, a variety of carriers well-known in the art may beused. Such a carrier includes excipients such as crystalline cellulose,lactose, starch, hydrogenated vegetable oil, kaoline and talc; binderssuch as powdered acacia, powdered tragacanth gum and gelatin;disintegrators such as calcium carmelose and agar.

Capsule may be prepared by blending an active ingredient with a varietyof the above carriers as usual and filling the resulting blend into, forexample, a hard or soft gelatin capsule or the like.

For preparing injection, solution, emulsion and suspension aresterilized and preferably isotonic with blood. It may be prepared usingdiluents commonly used in the art; for example, water, ethanol,macrogol, propylene glycol, ethoxylated isostearyl alcohol,polyoxyisostearyl alcohol and polyoxyethylene sorbitan fatty acidesters. The pharmaceutical preparation may contain sodium chloridenecessary to prepare an isotonic solution, glucose or glycerin, as wellas usual solubilizers, buffers and soothing agents.

Suppository may be formed using a variety of well-known carriers; forexample, semi-synthetic glyceride, cocoa butter, higher alcohols, higheralcohol esters and polyethylene glycol.

Furthermore, the pharmaceutical composition may contain coloring agents,preservatives, perfumes, flavors, sweeteners and/or other drugs.

The amount of the active ingredient in the pharmaceutical composition ofthis invention may be, as appropriate, selected from a wide range withno limitations, and is generally about 1 to 70% by weight in thecomposition, preferably about 5 to 50% by weight.

An administration route of the pharmaceutical composition is notlimited, and selected depending on patient's age, sex, severity ofdisease and other conditions. For example, tablet, pill, solution,suspension, emulsion, granule and capsule may be orally administered;injection may be intravenously administered solely or in combinationwith a common infusion fluid such as glucose, amino acids and the like,or if necessary, intramuscularly, subcutaneously or intraperitoneally asa sole preparation. Suppository may be intrarectally administered.

Dose of the pharmaceutical preparation of this invention may beselected, depending on their dosage form, patient's age, sex andseverity of disease, and other conditions, as appropriate, but theamount of the active ingredient may be generally about 0.0001 to 100mg/kg a day. It is recommended that a unit dosage form may contain about0.001 to 1000 mg of the active ingredient.

The compound represented by formula (1) or (13) of this invention or asalt thereof exhibits no or a mall toxicity which is acceptable as theanticancer agent at the dose showing pharmacological effects.

EXAMPLES

This invention will be specifically illustrated with, but is not limitedto, the following examples, where the numbers in parentheses indicatethose of the compounds shown in the above detailed description.

Example 1 Preparation ofN-(2-Aminophenyl)-4-(N-benzoylaminomethyl)benzamide Hydrochloride (Table1: Hydrochloride of Compound 1)

(1-1) To a suspension of 21.16 g of 4-aminomethylbenzoic acid (140 mmol)in 450 mL of dichloromethane was added 42 mL of triethylamine (300mmol). Under ice-cooling, 60.4 g of trifluoroacetic anhydride (287 mmol)in 50 mL of dichloromethane were added dropwise, maintaining the innertemperature at 3 to 8° C., and then the mixture was stirred four 3hours. The reaction mixture was poured into a saturated aqueous sodiumbicarbonate solution, and was acidified with 10% hydrochloric acid. Thegel precipitate was collected by filtration and dried to give 30.4 g of4-(N-trifluoroacetylaminomethyl)benzoic acid (Yield: 87.8%) as anopalescent solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.47 (2H, d, J=5.8 Hz), 7.39 (2H, d,J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz), 10.08 (1H, t, J=5.8 Hz), 12.95 (1H,br.s.).

(1-2) To a solution of 108 g of o-phenylenediamine (1.0 mol) in 1000 mLof dioxane was added 500 mL of 1N sodium hydroxide aq., and then 218 gof tert-butyldicarbonate (1.1 mol) in 500 mL of dioxane underice-cooling. After stirring for 6 hours at room temperature, the mixturewas left overnight. The mixture was concentrated to ½ volume byevaporation, and extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried and evaporated. The residue waspurified by column chromatography (eluent: chloroform) to give a solid,which was then washed with diethyl ether to give 68.4 g ofN-tert-butoxycarbonyl-o-phenylenediamine (Yield: 32.8%) as a whitesolid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 3.75 (2H, s), 6.26 (1H, s),6.77 (1H, d, J=8.1 Hz), 6.79 (1H, dd, J=7.3, 8.1 Hz), 7.00 (1H, dd,J=7.3, 8.1 Hz), 7.27 (1H, d, J=8.1 Hz).

(1-3) To a suspension of 30 g of the compound from the process (1-1)(121 mmol) in 200 mL of dichloromethane were slowly added dropwise 21 gof oxalyl chloride (165 mmol) with intermittently adding DMF (0.1 mL per2 mL addition), maintaining the inner temperature within 10 to 15° C. byice-cooling. After completion of the addition, the mixture was stirreduntil bubble generation ceased, and then at 40° C. for an additionalhour. After evaporation, excess oxalyl chloride was azeotropicallyremoved with toluene, and then the residue was redissolved in 100 mL ofdichloroethane. The prepared acid chloride solution was added dropwiseto a solution of 22.88 g of the compound from the process (1-2) (110mmol) in 100 mL of dichloromethane and 200 mL of pyridine, maintainingthe inner temperature within 7 to 9° C. by ice-cooling.

After addition, the mixture was warmed to room temperature, and was leftovernight. After adding saturated sodium bicarbonate aq. to the reactionmixture, the resulting mixture was extracted with chloroform, and theorganic layer was washed with saturated brine, dried and evaporated. Tothe residue was added methanol-diisopropyl ether, and the precipitatedsolid was collected by filtration and dried to give 28.1 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-(N-trifluoroacetylaminomethyl)benzamide(Yield: 58%) as a light yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (9H, s), 4.48 (2H, d, J=5.9 Hz),7.12-7.23 (2H, m), 7.44 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz), 7.94(2H, d, J=8.1 Hz), 8.68 (1H, br.s), 9.83 (1H, s), 10.10 (1H, br.t, J=5.9Hz).

(1-4) To a suspension of 13.12 g of the compound from the process (1-3)(30 mmol) in 120 mL of methanol and 180 mL of water were added 4.70 g ofpotassium carbonate (34.0 mmol), and the mixture was heated withstirring at 70° C. for 4 hours. It was extracted with chloroform, andthe organic layer was washed with saturated brine, dried, evaporated anddried to give 10.3 g of4-aminomethyl-N-[2-(N-tert-butoxycarbonyl)aminophenyl]benzamide (Yield:quantitative) as a light yellow amorphous solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.80 (2H, s), 7.13-7.23 (2H, m),7.48-7.58 (4H, m), 7.90 (2H, d, J=8.1 Hz), 8.69 (1H, br.s), 9.77 (1H,br.s).

(1-5) To a solution of 0.11 g of the compound from the process (1-4)(0.44 mmol) in 5 mL of pyridine was added 0.08 g of benzoyl chloride(0.53 mmol), and the mixture was gradually warmed to room temperatureand then stirred for 8 hours. Saturated sodium bicarbonate aq. wasadded, and then the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and evaporated. Theresidue was washed with diisopropyl ether, and the solid obtained wasdried to give 0.14 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-(N-benzoylaminomethyl)benzamide(Yield: 71.4%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (9H, s), 4.56 (2H, d, J=5.9 Hz),7.11-7.22 (2H, m), 7.46-7.56 (7H, m), 7.90-7.94 (4H, m), 8.67 (1H, s),9.15 (1H, t, J=5.9 Hz), 9.81 (1H, s).

(1-6) To a solution of 0.10 g of the compound from the process (1-5)(0.224 mmol) in 5 mL of dioxane and 1 mL of methanol was added 5 mL of4N hydrochloric acid-dioxane, and the mixture was stirred at roomtemperature for 7 hours. To the residue after evaporation was addeddiisopropyl ether, and the formed solid was collected by filtration anddried to give 0.08 g ofN-(2-aminophenyl)-4-(N-benzoylaminomethyl)benzamide hydrochloride(Yield: 93%) as a light brown solid.

mp: 206-209° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.57 (2H, d, J=5.8Hz), 7.27-7.38 (4H, m), 7.47-7.59 (5H, m), 7.92 (1H, d, J=8.1 Hz), 8.05(1H, d, J=8.1 Hz), 9.19 (1H, t, J=5.8 Hz), 10.38 (1H, br.s); IR (KBr,cm⁻¹): 3286, 3003 (br.), 1630, 1551, 1492, 1306, 1250, 749, 695.

As described in Example 1, the compounds of Examples 2 to 44 wereprepared, each of whose melting point (mp), ¹H NMR data and/or IR dataare described below.

Example 2 N-(2-Aminophenyl)-4-[N-(2-chlorobenzoyl)aminomethyl]benzamide(Table 1: Compound 14)

mp: 201-204° C. (dec.). ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.52 (2H, t,J=5.9 Hz), 4.89 (2H, br.s), 6.60 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 6.78(1H, dd, J=1.5, 8.1 Hz), 6.97 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.17 (1H,d, J=8.1 Hz), 7.38-7.54 (6H, m), 7.97 (2H, d, J=8.1 Hz), 9.06 (1H, br.t,J=5.9 Hz), 9.63 (1H, br.s); IR (KBr) cm⁻¹: 3268, 1649, 1458, 1304, 748.

Example 3 N-(2-Aminophenyl)-4-[N-(2-nitrobenzoyl)aminomethyl]benzamideHydrochloride (Table 1: Hydrochloride of Compound 18)

mp: 210-212° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) ppm: 4.55 (2H, t,J=5.9 Hz) 7.20-7.40 (3H, m), 7.50-7.60 (1H, m), 7.53 (2H, d, J=8.1 Hz),7.60-7.70 (2H, m), 7.83 (1H, ddd, J=1.5, 8.1, 8.1 Hz), 8.00-8.10 (3H,m), 9.34 (1H, t, J=5.9 Hz) 10.43 (1H, br.s); IR (KBr)cm⁻¹: 3283,2500-3000 (br.), 1648, 1534, 1461, 1362, 1314, 754, 701.

Example 4 N-(2-Aminophenyl)-4-[N-(4-methylbenzoyl)aminomethyl]benzamideHydrochloride (Table 1: Hydrochloride of Compound 28)

mp: (amorphous). ¹H NMR (270 MHz, DMSO-d₆) ppm: 2.37 (3H, s), 4.56 (2H,d, J=5.0 Hz), 7.20-7.30 (6H, m), 7.47 (4H, d, J=8.8 Hz), 7.82 (2H, d,J=8.8 Hz), 8.03 (2H, d, J=8.8 Hz), 9.09 (1H, t, J=5 Hz), 10.36 (1H,br.s); IR (KBr)cm⁻¹: 3269 (br.), 2861 (br.), 1743, 1636, 1534, 1505,1456, 1308, 1120, 753.

Example 5 N-(2-Aminophenyl)-4-[N-(3-methoxybenzoyl)aminomethyl]benzamide(Table 1: Compound 30)

mp: 182-185° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.81 (3H, s), 4.54(2H, d, J=5.9 Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J=6.6, 7.3 Hz), 6.78(1H, d, J=7.3 Hz), 6.97 (1H, dd, J=6.6, 7.3 Hz), 7.11 (1H, dd, J=1.5,8.1 Hz), 7.16 (1H, d, J=7.3 Hz), 7.35-7.51 (5H, m), 7.94 (2H, d, J=8.1Hz), 9.12 (1H, br.t, J=5.9 Hz), 9.63 (1H, br.s); IR (KBr)cm⁻¹: 3301,1637, 1524, 1489, 1457, 1314, 1248, 752.

Example 6 N-(2-Aminophenyl)-4-[N-(4-methoxybenzoyl)aminomethyl]benzamide(Table 1: Compound 31)

mp: 149-151° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.82 (3H, s), 4.53(2H, d, J=5.9 Hz), 4.88 (2H, s), 6.59 (1H, dd, J=7.3, 7.3 Hz), 6.77 (1H,d, J=8.1 Hz), 6.94-7.00 (1H, m), 7.02 (2H, d, J=8.8 Hz), 7.16 (1H, d,J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.89 (2H, d, J=8.8 Hz), 7.94 (2H, d,J=8.1 Hz), 8.98 (1H, br.t, J=5.9 Hz), 9.61 (1H, br.s); IR (KBr)cm⁻¹:3297, 1630, 1527, 1505, 1457, 1256, 1177, 1024, 843, 749.

Example 7N-(2-Aminophenyl)-4-[N-(3,4,5-trimethoxybenzoyl)aminomethyl]benzamide(Table 1: Compound 33)

mp: 208-210° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.71 (3H, s),3.83 (6H, s), 4.55 (2H, d, J=5.9 Hz), 4.88 (2H, br.s), 6.60 (1H, dd,J=7.3, 8.1 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=6.6, 8.1 Hz),7.16 (1H, d, J=8.1 Hz), 7.26 (2H, s), 7.44 (2H, d, J=8.1 Hz), 7.95 (2H,d, J=8.8 Hz), 9.07 (1H, t, J=5.9 Hz), 9.62 (1H, br.s); IR (KBr)cm⁻¹:3267, 1635, 1582, 1457, 1237, 1132, 755.

Example 8N-(2-Aminophenyl)-4-[N-[4-(N,N-dimethyl)aminobenzoyl]aminomethyl]benzamide(Table 1: Compound 36)

mp: 216-219° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.98 (6H, s),4.51 (2H, d, J=5.9 Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J=8.1, 8.1 Hz),6.71 (2H, d, J=8.8 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=7.3Hz), 7.41 (2H, d, J=8.1 Hz), 7.78 (2H, d, J=8.8 Hz), 7.93 (2H, d, J=8.1Hz), 8.77 (1H, t, J=5.9 Hz), 9.63 (1H, br.s). IR (KBr)cm⁻¹: 3301, 1632,1519, 1457, 1298, 754.

Example 9N-(2-Aminophenyl)-4-[N-(4-trifluoromethylbenzoyl)aminomethyl]benzamide(Table 1: Compound 42)

mp: 243-246° C. ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.58 (2H, d, J=5.9 Hz),4.88 (2H, br.s), 6.59 (1H, dd, J=6.6, 7.3 Hz), 6.77 (1H, d, J=8.1 Hz),6.94 (1H, dd, J=5.9, 6.6 Hz), 7.16 (1H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1Hz), 7.88 (2H, d, J=8.8 Hz), 7.95 (2H, d, J=8.1 Hz), 8.11 (2H, d, J=8.1Hz), 9.38 (1H, t, J=5.9 Hz), 9.64 (1H, br.s); IR (KBr)cm⁻¹: 3301, 1640,1549, 1523, 1458, 1334, 1162, 1120, 1070, 856, 750.

Example 10N-(2-Aminophenyl)-4-[N-(4-carboxybenzoyl)aminomethyl]benzamideHydrochloride (Table 1: Hydrochloride of Compound 45)

mp: (amorophous). ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.58 (2H, d, J=5.9Hz), 7.29-7.37 (3H, m), 7.49 (3H, d, J=8.1 Hz), 8.02-8.06 (6H, m), 9.36(1H, t, J=5.9 Hz), 10.4 (1H, br.s); IR (KBr)cm⁻¹: 3432 (br.), 1718,1637, 1542, 1499, 1303 (br.), 1116, 1018, 757.

Example 11N-(2-Aminophenyl)-4-[N-(4-methoxycarboxybenzoyl)aminomethyl]benzamide(Table 1: Compound 46)

mp: 204-209° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.89 (3H, s),4.57 (2H, d, J=5.9 Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J=6.6, 7.3 Hz),6.78 (2H, d, J=7.3 Hz), 6.97 (1H, ddd, J=1.5, 6.6, 7.3 Hz), 7.16 (1H, d,J=7.3 Hz), 7.45 (2H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz), 8.03 (2H, d,J=8.8 Hz), 8.07 (2H, d, J=8.8 Hz), 9.35 (1H, t, J=5.9 Hz), 9.64 (1H,br.s); IR (KBr)cm⁻: 3287 (br.), 1721, 1634, 1281, 1113, 750, 703.

Example 12 N-(2-Aminophenyl)-4-(N-picolinoylaminomethyl)benzamide (Table1: Compound 173)

mp: 173-178° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.57 (2H, d,J=6.6 Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J=7.3, 8.1 Hz), 6.77 (1H, d,J=8.1 Hz), 6.96 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=7.3 Hz), 7.44(2H, d, J=8.1 Hz), 7.60-7.65 (1H, m), 7.93 (2H, d, J=8.1 Hz), 7.98-8.08(2H, m), 8.67 (1H, d, J=4.4 Hz), 9.45 (1H, t, J=6.6 Hz), 9.61 (1H, brs); IR (KBr)cm⁻¹: 3330, 1656, 1634, 1523, 1456, 1294, 752.

Example 13N-(2-Aminophenyl)-4-(N-(6-methylpicolinoyl)aminomethyl]benzamide (Table1: Compound 178)

mp: 172-173° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.51 (3H, s), 4.57(2H, d, J=6.6 Hz), 5.0 (2H, br.s), 6.61 (1H, dd, J=7.3, 8.1 Hz), 6.79(1H, d, J=7.3 Hz), 6.98 (1H, dd, J=7.3, 8.1 Hz), 7.17 (1H, d, J=7.3 Hz),7.44 (2H, d, J=8.1 Hz), 7.43-7.49 (1H, m), 7.84-7.90 (2H, m), 7.94 (2H,d, J=8.1 Hz), 9.27 (1H, t, J=5.9 Hz), 9.64 (1H, br.s); IR (KBr)cm⁻¹:3331, 1675, 1634, 1594, 1523, 1454, 1307, 1292, 750.

Example 14 N-(2-Aminophenyl)-4-(N-nicotinoylaminomethyl)benzamide (Table1: Compound 71)

mp: 193-196° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.58 (2H, d), 4.88(2H, br.s), 6.60 (1H, t), 6.78 (1H, d), 6.97 (1H, t), 7.16 (1H, d), 7.46(2H, d), 7.53 (1H, dd), 7.95 (2H, d), 8.24 (1H, ddd), 8.73 (1H, dd),9.07 (1H, d), 9.32 (1H, br.t), 9.63 (1H, br.s) IR (KBr)cm⁻¹: 3301, 1639,1522, 1457, 1314, 749, 705.

Example 15N-(2-Aminophenyl)-4-[N-(2-methylnicotinoyl)aminomethyl]benzamide (Table1: Compound 141)

mp: 191-194° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.53 (3H, s),4.53 (2H, d, J=5.9 Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J=6.6, 8.1 Hz),6.78 (1H, d, J=7.3 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.17 (1H, d, J=7.3Hz), 7.29 (1H, dd, J=5.1, 8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.77 (1H, dd,J=1.5, 8.1 Hz), 7.97 (2H, d, J=8.1 Hz), 8.51 (1H, dd, J=1.5, 5.1 Hz),9.06 (1H, t, J=5.9 Hz), 9.64 (1H, s); IR (KBr)cm⁻¹: 3261, 1642, 1523,1310, 753.

Example 16N-(2-Aminophenyl)-4-[N-(6-methylnicotinoyl)aminomethyl]benzamide (Table1: Compound 143)

mp: 186-190° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.36 (3H, s),4.56 (2H, d, J=5.9 Hz), 4.88 (2H, s), 6.60 (1H, dd, J=7.4, 7.8 Hz), 6.78(1H, d, J=7.8 Hz), 6.97 (1H, dd, J=6.9, 6.9 Hz), 7.16 (1H, d, J=7.4 Hz),7.37 (1H, d, J=8.3 Hz), 7.45 (2H, d, J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz),8.13 (1H, dd, J=2.0, 8.3 Hz), 8.96 (1H, s), 9.24 (1H, t, J=5.9 Hz), 9.63(1H, br.s); IR (KBr)cm⁻¹: 3302, 1636, 1602, 1523, 1489, 1457, 1313, 751.

Example 17N-(2-Aminophenyl)-4-[N-(2-chloronicotinoyl)aminomethyl]benzamide (Table1: Compound 154)

mp: 176-178° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.54 (2H, t,J=5.9 Hz), 4.90 (2H, br.s), 6.60 (1H, ddd, J=1.5, 7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97 (1H, ddd, J=1.5, 7.3, 7.3 Hz), 7.18 (1H, d,J=8.1 Hz), 7.48-7.54 (3H, m), 7.94-7.99 (3H, m), 8.49 (1H, dd, J=2.1,5.1 Hz), 9.23 (1H, br.t, J=5.9 Hz), 9.65 (1H, br.s); IR (KBr)cm⁻¹: 3264,1649, 1524, 1400, 1309, 751.

Example 18N-(2-Aminophenyl)-4-[N-(6-chloronicotinoyl)aminomethyl]benzamide (Table1: Compound 156)

mp: 205-208° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 5.57 (2H, d,J=5.9 Hz), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.96(1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1 Hz),7.66 (1H, d, J=8.8 Hz), 7.95 (2H, d, J=8.1 Hz), 8.27-8.32 (1H, m), 8.90(1H, d, J=2.1 Hz), 9.38 (1H, t, J=5.9 Hz), 9.63 (1H, s); IR (KBr)cm⁻¹:3318 (br.), 2929, 1646, 1590, 1525, 1503, 1454, 1108, 745.

Example 19 N-(2-Aminophenyl)-4-(N-isonicotinoylaminomethyl)benzamide(Table 1: Compound 183)

mp: 234-237° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.57 (2H, t,J=5.9 Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J=6.6, 7.3 Hz), 6.78 (1H, d,J=8.1 Hz), 6.96 (1H, dd, J=7.3, 7.3 Hz), 7.16 (1H, d, J=7.3 Hz), 7.45(2H, d, J=8.1 Hz), 7.81 (2H, d, J=1.5, 4.4 Hz), 7.95 (2H, d, J=8.1 Hz),8.75 (2H, d, J=6.6 Hz), 9.41 (1H, t, J=5.9 Hz), 9.62 (1H, br.s); IR(KBr)cm⁻¹: 3298, 1646, 1550, 1525, 1457, 1304, 843, 760, 695.

Example 20N-(2-Aminophenyl)-4-[N-(pyrazin-2-yl)carbonylaminomethyl]benzamide(Table 1: Compound 191)

mp: 207° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.58 (2H, d, J=5.9Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J=7.3, 7.3 Hz), 6.77 (1H, d, J=8.1Hz), 6.94 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.15 (1H, d, J=7.3 Hz), 7.45(2H, d, J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz), 8.77 (1H, d, J=1.5 Hz), 8.90(1H, d, J=2.1 Hz), 9.21 (1H, s), 9.55-9.61 (2H, m); IR (KBr)cm⁻¹: 3368(br.), 1657, 1524, 1455, 1295, 1023, 751.

Example 21N-(2-Aminophenyl)-4-[N-(thiophen-2-yl)carbonylaminomethyl]benzamide(Table 1: Compound 201)

mp: 202-205° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.52 (2H, t,J=5.9 Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J=6.6.7.3 Hz), 6.78 (1H, d,J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.15-7.18 (2H, m), 7.43 (2H, d,J=8.1 Hz), 7.78 (1H, d, J=4.4), 7.82 (1H, d, J=3.7 Hz), 7.95 (2H, d,J=8.1 Hz), 9.12 (1H, br.t, J=5.9 Hz), 9.62 (1H, br.s); IR (KBr)cm⁻¹:3306, 1633, 1523, 1456, 1297, 750, 716.

Example 22N-(2-Aminophenyl)-4-[N-(furan-2-yl)carbonylaminomethyl]benzamide (Table1: Compound 205)

mp: 197° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.59 (2H, d, J=6.6Hz), 4.86 (2H, br.s), 6.59 (1H, dd, J=6.6, 6.6 Hz), 6.63 (1H, dd, J=1.5,3.6 Hz), 6.78 (1H, d, J=8.1 Hz), 6.96 (1H, dd, J=7.3, 6.6 Hz), 7.10-7.20(2H, m), 7.41 (2H, d, J=8.1 Hz), 7.84 (1H, s), 7.94 (2H, d, J=1 Hz),9.00 (1H, br.t, J=5.9 Hz), 9.62 (1H, s); IR (KBr)cm⁻¹: 3245, 1651, 1573,1545, 1323, 1241, 745.

Example 23N-(2-Aminophenyl)-4-[N-(pyrrol-2-yl)carbonylaminomethyl]benzamide (Table1: Compound 209)

mp: 216-220° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.50 (2H, d,J=5.9 Hz), 4.88 (2H, br.s), 6.10 (1H, dd, J=2.1, 5.9 Hz), 6.59 (1H, dd,J=7.3, 7.3 Hz), 6.77 (1H, dd, J=1.5, 8.1 Hz), 6.84-6.88 (2H, m), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16 (1H, d, J=7.3 Hz), 7.41 (2H, d,J=8.1 Hz), 7.94 (2H, d, J=8.1 Hz), 8.62 (1H, br.t, J=5.9 Hz), 9.62 (1H,br.s); IR (KBr)cm⁻¹: 3275, 1655, 1584, 1534, 1458, 1316, 747.

Example 24N-(2-Aminophenyl)-4-[N-(N′-methyl-1H-pyrrol-2-yl)carbonylaminomethyl]benzamide(Table 1: Compound 210)

mp: 177-179° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.84 (3H, s),4.46 (2H, d, J=5.9 Hz), 4.88 (2H, br.s), 6.03 (1H, dd, J=2.1, 4.4 Hz),6.59 (1H, dd, J=8.1, 8.1 Hz), 6.77 (1H, d, J=8.1 Hz), 6.84-6.97 (2H, m),7.16 (1H, d, J=7.3 Hz), 7.41 (2H, d, J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz),8.61 (1H, t, J=5.9 Hz), 9.62 (1H, br.s); IR (KBr)cm⁻¹: 3325 (br.), 1630,1551, 1520, 1507, 1324, 1265, 1154, 740.

Example 25N-(2-Aminophenyl)-4-[N-(isoxazol-5-yl)carbonylaminomethyl]benzamide(Table 1: Compound 212)

mp: 183-185° C. (dec.); ¹H NMR (270 MHz. DMSO-d₆) δ ppm: 4.53 (2H, d,J=6.6 Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d,J=7.3 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.12 (1H, d, J=2.1 Hz), 7.16(1H, d, J=8.1 Hz), 7.44 (2H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz), 8.76(1H, d, J=1.5 Hz), 9.61 (1H, t, J=5.9 Hz), 9.64 (1H, br.s); IR(KBr)cm⁻¹: 3278 (br.), 1636, 1576, 1522, 1458, 1220, 749.

Example 26N-(2-Aminophenyl)-4-[N-(3-methylisothiazol-5-yl)carbonylaminomethyl]benzamide(Table 1: Compound 213)

mp: 168-169° C. ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.47 (3H, s), 4.54 (2H,d, J=5.9 Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H,d, J=7.3 Hz), 6.97 (1H, ddd, J=1.0, 7.3, 8.1 Hz), 7.17 (1H, d, J=7.3Hz), 7.44 (2H, d, J=8.1 Hz), 7.73 (1H, s), 7.96 (2H, d, J=8.1 Hz), 9.44(1H, t, J=5.9 Hz), 9.64 (1H, br.s); IR (KBr)cm⁻¹: 3310, 1637, 1503,1294, 751.

Example 27N-(2-Aminophenyl)-4-[N-(imidazol-4-yl)carbonylaminomethyl]benzamide(Table 1: Compound 214)

mp: (amorphous). ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.49 (2H, d, J=6.4Hz), 4.87 (2H, br.s), 6.59 (1H, dd, J=6.9, 6.9 Hz), 6.77 (1H, d, J=6.9Hz), 6.96 (1H, dd, J=7.4, 7.4 Hz), 7.16 (1H, d, J=6.9 Hz), 7.41 (2H, d,J=6.9 Hz), 7.64 (1H, br.s), 7.73 (1H, br.s), 7.92 (2H, d, J=6.9 Hz),8.56 (1H, br.t, J=6.4 Hz), 9.61 (1H, s), 12.5 (1H, br.s); IR (KBr)cm⁻¹:3278 (br.), 1636, 1576, 1522, 1458, 1220, 749.

Example 28N-(2-Aminophenyl)-4-[N-(3-aminophenyl)acetylaminomethyl]benzamide (Table1: Compound 23)

mp: 171-176° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.34 (2H, d, J=5.9Hz), 5.24 (4H, br.s), 6.48-6.63 (4H, m), 6.78-6.81 (1H, m), 6.94-7.00(2H, m), 7.18 (1H, d, J=8.1 Hz), 7.34 (2H, d, J=8.1 Hz), 7.92 (2H, d,J=8.1 Hz), 8.50 (1H, t, J=5.9 Hz), 9.61 (1H, s).

Example 29N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)acetylaminomethyl]benzamide (Table1: Compound 74)

mp: 127° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.84 (2H, s), 4.40 (2H, d,J=5.8 Hz), 7.15-7.29 (3H, m), 7.37 (1H, d, J=6.6 Hz), 7.43 (2H, d, J=8.8Hz), 7.96 (1H, m), 7.98 (2H, d, J=8.8 Hz), 8.40 (1H, d, J=8.8 Hz),8.79-8.87 (3H, m), 10.20 (1H, s).

Example 30N-(2-Aminophenyl)-4-[N-[3-(pyridin-3-yl)propionyl]aminomethyl]benzamide(Table 1: Compound 75)

mp: 183-186° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.51 (2H, t, J=7.3Hz), 2.88 (2H, d, J=7.3 Hz), 4.31 (2H, d, J=5.9 Hz), 4.89 (2H, br.s),6.60 (1H, dd, J=7.3, 8.1 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, ddd,J=1.5, 7.3, 8.1 Hz), 7.16 (1H, d, J=8.1 Hz), 7.23 (2H, d, J=8.8 Hz),7.28-7.33 (1H, m), 7.63 (1H, d, J=8.1 Hz), 7.89 (2H, d, J=8.1 Hz),8.41-8.45 (3H, m), 9.62 (1H, br.s); IR (KBr)cm⁻¹: 3407, 3313, 1640,1552, 1522, 1456, 1309, 746, 717.

Example 31N-(2-Aminophenyl)-4-[N-[4-(pyridin-3-yl)-1,4-dioxobutyl]aminomethyl]benzamide(Table 1: Compound 100)

mp: 145-147° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.37-2.50 (2H,m), 2.62-2.68 (2H, m), 4.13 (2H, s), 4.86 (2H, s), 6.56-6.61 (1H, m),6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.10-7.39 (4H, m), 7.43-7.46 (1H,m), 7.78 (2H, d, J=8.1 Hz), 8.60-8.64 (1H, m), 9.58 (1H, s); IR(KBr)cm⁻¹: 3348, 1691, 1655, 1534, 1508, 1458, 1395, 1315, 1083, 746.

Example 32N-(2-Aminophenyl)-4-[N-(5-chloropyridin-3-yl)oxyacetylaminomethyl]benzamide(Table 1: Compound 158)

mp: 199-201° C. ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.43 (2H, d, J=6.6 Hz),4.75 (2H, s), 4.87 (2H, br. s), 6.60 (1H, dd, J=7.3, 8.1 Hz), 6.78 (1H,d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=8.1 Hz), 7.37(2H, d, J=8.1 Hz), 7.59 (1H, d, J=2.2 Hz), 7.93 (2H, d, J=8.1 Hz), 8.25(1H, d, J=1.5 Hz), 8.81 (1H, t, J=6.6 Hz), 9.64 (1H, s); IR (KBr)cm⁻¹:3288, 3058, 1675, 1633, 1523, 1457, 1314, 912, 755.

Example 33N-(2-Amino-5-methoxyphenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide(Table 1: Compound 175)

mp: 141-144° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.66 (3H, s), 4.43(2H, d, J=5.9 Hz), 4.49 (2H, br.s), 4.68 (2H, s), 6.62 (1H, dd, J=2.9,8.8 Hz), 6.75 (1H, d, J=8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 7.37 (4H, m),7.92 (2H, d, J=8.8 Hz), 8.21 (1H, dd, J=1.5, 4.4 Hz), 8.35 (1H, d, J=2.7Hz), 8.81 (1H, s), 9.65 (1H, s).

Example 34N-(2-Aminophenyl)-4-[N-[3-(pyridin-3-yl)-1,3-dioxopropyl]aminomethyl]benzamide(Table 1: Compound 98)

mp: 204-206° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.08 (4/3H, s), 4.39(4/3H, d, J=5.9 Hz), 4.49 (2/3H, d, J=5.9 Hz), 4.90 (2H, br.s), 5.93(1/3H, s), 6.60 (1H, t, J=7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, t,J=7.3 Hz), 7.16 (1H, d, J=7.3 Hz), 7.3-7.7 (3H, m), 7.8-8.4 (3H, m),8.6-9.2 (3H, m), 9.64 (1H, s), 14.74 (1/3H, s), (2:1 equilibriummixture); IR (KBr)cm⁻1: 3282, 1690, 1645, 1527, 1421, 1314, 1217, 1028,994, 911, 753, 701.

Example 35N-(2-Aminophenyl)-4-[N-[N-(pyridin-3-yl)aminoacetyl]aminomethyl]benzamide(Table 1: Compound 96)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.77 (2H, d, J=6.6Hz), 4.37 (2H, d, J=5.9 Hz), 4.87 (2H, br.s), 6.27 (1H, t, J=5.9 Hz),6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d, 7.3 Hz) 6.87 (1H, d, J=8.1Hz), 6.96 (1H, dd, J=7.3, 8.1 Hz), 7.09 (1H, d, J=4.4 Hz), 7.12 (1H, d,J=4.4 Hz), 7.16 (1H, d, J=8.1 Hz), 7.33 (2H, d, J=8.8 Hz), 7.81 (1H, d,J=4.4 Hz), 7.91 (2H, d, J=7.3 Hz), 7.99 (1H, d, J=2.9 Hz), 8.59 (1H,br.t, J=5.1 Hz), 9.63 (1H, br.s); IR (KBr)cm⁻¹: 3350, 1658, 1525, 1502,1314, 750.

Example 36N-(2-Aminophenyl)-4-[N-(2-aminothiazol-4-yl)acetylaminomethyl]benzamide(Table 1: Compound 220)

mp: (amorphous). ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.34 (2H, s), 4.35(2H, d, J=5.9 Hz), 4.87 (2H, s), 6.25 (1H, s), 6.59 (1H, dd, J=7.3, 7.3Hz), 6.78 (1H, d, J=7.3 Hz), 6.87 (2H, s), 6.96 (1H, dd, J=7.3, 7.3 Hz),7.16 (1H, d, J=7.3 Hz), 7.37 (2H, d, J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz),8.44 (1H, t, J=5.9 Hz), 9.62 (1H, s).

Example 37N-(2-Aminophenyl)-4-[N-(quinolin-6-yl)carbonylaminomethyl]benzamide(Table 1: Compound 231)

mp: 209-210° C. ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.62 (2H, d, J=5.9 Hz),4.88 (2H, s), 6.60 (1H, t, J=7.7 Hz), 6.78 (1H, d, J=7.3 Hz), 6.95 (1H,d, J=7.3 Hz), 7.17 (1H, d, J=7.3 Hz), 7.49 (2H, d, J=8.8 Hz), 7.62 (1H,dd, J=4.4, 8.1 Hz), 7.96 (2H, d, J=8.8 Hz), 8.10 (1H, d, J=8.8 Hz), 8.23(1H, dd, J=2.2, 8.8 Hz), 8.38 (1H, m), 8.49 (1H, d, J=8.1 Hz), 8.58 (1H,s), 8.99 (1H, s), 9.64 (1H, s); IR (KBr)cm⁻¹: 3301, 1640, 1614, 1545,1496, 1312, 910, 853, 745.

Example 38N-(2-Aminophenyl)-4-[N-(furo[3,2-b]pyridin-2-yl)carbonylaminomethyl]benzamide(Table 1: Compound 233)

mp: 191° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.58 (2H, d, J=5.9Hz), 4.88 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93-6.99 (1H,m), 7.15-7.25 (1H, m), 7.45-7.52 (3H, m), 7.74 (1H, s), 7.95 (2H, d,J=8.1 Hz), 8.13 (1H, d, J=8.8 Hz), 8.63 (1H, d, J=3.7 Hz), 9.54 (1H, t,J=5.9 Hz), 9.64 (1H, s); IR (KBr)cm⁻¹: 3406, 1662, 1529, 1507, 1420,1313, 1209, 1139, 1170, 1139, 924, 741.

Example 39N-(2-Aminophenyl)-4-[N-(furo[2,3-c]pyridin-2-yl)carbonylaminomethyl]benzamide(Table 1: Compound 234)

mp: 210° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.58 (2H, J=6.6Hz), 4.87 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93-6.99 (1H,m), 7.14-7.17 (1H, m), 7.47 (2H, d, J=8.1 Hz), 7.66 (1H, s), 7.82 (1H,d, J=4.4 Hz), 7.96 (2H, d, J=8.1 Hz), 8.48 (1H, d, J=5.1 Hz), 9.06 (1H,s), 9.60-9.64 (2H, m); IR (KBr)cm⁻¹: 3320, 1653, 1632, 1598, 1457, 1424,1308, 1187, 1033, 853, 749.

Example 40N-(2-Hydroxyphenyl)-4-[N-[3-(pyridin-3-yl)propionyl]aminomethyl]benzamide(Table 1: Compound 125)

mp: (amorphous); ¹H NMR (270 MHz, CD₃OD) δ ppm: 2.61 (2H, t, J=7.3 Hz),3.00 (2H, t, J=7.3 Hz), 4.39 (2H, s), 7.04 (1H, ddd, J=1.5, 8.1, 8.1Hz), 7.25 (2H, d, J=8.1 Hz), 7.33 (1H, dd, J=5.1, 8.1 Hz), 7.69 (1H, d,J=8.1 Hz), 7.85 (2H, d, J=8.1 Hz), 7.86 (1H, d, J=8.1 Hz), 8.41 (2H,br.s); IR (neat)cm⁻¹: 3276, 1645, 1614, 1536, 1509, 1435, 1415, 1385,1333, 1280, 1247, 1091, 737.

Example 41N-(2-Hydroxyphenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide(Table 1: Compound 93)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆): 4.43 (2H, d, J=6.6 Hz), 4.69(2H, s), 6.83 (1H, t, J=6.6 Hz), 6.91 (1H, d, J=8.1 Hz), 7.68 (1H, d,J=6.6 Hz), 7.82 (2H, d, J=8.1 Hz), 8.21 (1H, d, J=4.4 Hz), 8.35 (1H, d,J=2.2 Hz), 8.81 (1H, t, J=6.6 Hz), 9.48 (1H, s), 9.75 (1H, s); IR(KBr)cm⁻¹: 3399, 1664, 1535, 1236, 1064.

Example 42N-(2-Hydroxyphenyl)-4-[N-(pyridin-3-yl)acetylaminomethyl]benzamide(Table 1: Compound 117)

mp: 201-202° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.56 (2H, s), 4.37(2H, d, J=5.9 Hz), 6.83 (1H, ddd, J=1.5, 8.1, 8.1 Hz), 6.92 (1H, br.d,J=8.1 Hz), 7.03 (1H, ddd, J=1.5, 8.1, 8.1 Hz), 7.34 (1H, dd, J=3.7, 8.1Hz), 7.37 (2H, d, J=8.1 Hz), 7.70 (2H, d, J=8.1 Hz), 7.91 (2H, d, J=8.1Hz), 8.45 (1H, br.d, J=3.7 Hz), 8.49 (1H, s), 8.73 (1H, t, J=5.9 Hz),9.47 (1H, s), 9.73 (1H, br.s); IR (KBr)cm⁻¹: 3272, 3067, 1661, 1647,1598, 1536, 1455, 1334, 1288, 1194, 1024, 742.

Example 43N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)oxyacetyl-N-[3-(pyridin-3-yl)propyl]aminomethyl]benzamide(Table 1: Compound 91)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.77-1.93 (2H, m),2.50-2.63 (2H, m), 3.16-3.30 (2H, m), 4.63 (1.2H, s), 4.71 (0.8H, s),4.88 (1.2H, s), 4.95 (0.8H, s), 5.05 (2H, s), 6.57-6.63 (1H, m),6.77-6.79 (1H, m), 6.94-7.00 (1H, m), 7.11-7.42 (5H, m), 7.58-7.64 (1H,m), 7.92-8.02 (2H, m), 8.15-8.43 (5H, m), 9.65 (0.6H, s), 9.69 (0.4H, s)(a mixture of rotational isomers).

Example 44N-(2-Aminophenyl)-4-[N-methyl-N-(pyridin-3-yl)oxyacetyl]aminomethylbenzamide(Table 1: Compound 92)

mp: 117-120° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.84 and 2.99 (total3H, s), 4.60 and 4.69 (total 2H, s), 4.90 (2H, br.s), 4.99 and 5.08(total 2H, s), 6.60 (1H, dd, J=7.3, 8.1 Hz), 6.78 (1H, d, J=8.1 Hz),6.97 (1H, dd, J=7.3, 7.3 Hz), 7.16 (1H, d, J=7.3 Hz), 7.30-7.43 (4H, m),7.95 and 8.01 (total 2H, d, J=8.1 Hz), 8.17 (1H, d, J=4.4 Hz), 8.31 (1H,d, J=2.9 Hz), 9.65 and 9.68 (total 1H, br.s) (a mixture of rotationalisomers); IR (kBr)cm⁻¹: 3298, 1665, 1501, 1425, 1310, 1276, 1254, 1078,799, 746, 703.

Example 45 Preparation ofN-(2-Aminophenyl)-4-[N-(pyridin-3-yl)oxamoylaminomethyl]benzamide (Table1: Compound 95)

(45-1) Ethyl N-(pyridin-3-yl)oxamate (388 mg, 2 mmol) and 638 mg of thecompound from the process (1-4) (2 mmol) were dissolved in ethanol, andthe mixture was heated with stirring at 40 to 50° C. for 2.5 hours. Theprecipitated crystals were collected by filtration and washed with 2 mLof ethanol and 3 mL of diethyl ether. The crystals were dried to give724 mg ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)oxamoylaminomethyl]benzamide(Yield: 74%).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (9H, s), 4.49 (2H, d, J=5.9 Hz),7.10-7.30 (2H, m), 7.35-7.57 (5H, m), 7.93 (2H, d, J=8.1 Hz), 8.21 (1H,br.d, J=5.1 Hz), 8.35 (1H, dd, J=1.5, 5.1 Hz), 8.68 (1H, br.s), 9.00(1H, d, J=2.9 Hz), 9.70 (1H, t, J=5.9 Hz), 9.82 (1H, s), 10.98 (1H,br.s).

(45-2) To a suspension of 720 mg of the compound from the process (45-1)in 8 mL of methanol was added 8 mL of 4N hydrochloric acid-dioxanesolution. After stirring for 3 hours, the mixture was poured into adiluted sodium hydroxide aq. to be basified, and the precipitatedcrystals were collected by filtration. The crystals were recrystallizedfrom THF/methanol=1:1, to give 280 mg of the desired product.

mp: 254-258° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.67 (2H, d,J=5.9 Hz), 4.89 (2H, br.s), 6.59 (1H, dd, J=7.3 Hz), 6.77 (1H, d, J=8.1Hz), 6.97 (1H, dd, J=6.6, 7.3 Hz), 7.16 (1H, d, J=8.1 Hz), 7.38-7.44(1H, m), 7.43 (2H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz), 8.18-8.24 (1H,m), 8.34 (1H, dd, J=1.5, 4.4 Hz), 9.00 (1H, d, J=2.1 Hz), 9.63 (1H, s),9.69 (1H, br.t, J=6.6 Hz), 10.97 (1H, br.s); IR (KBr.cm⁻¹): 3312, 3270,1663, 1636, 1521, 1312, 1296, 1019.

Example 46 Preparation ofN-(2-Aminophenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide(Table 1: Compound 61)

(46-1) To a suspension of 0.22 g of sodium hydride (60% oil dispersion,5.5 mmol) in 2 mL of DMF was added dropwise a solution of 0.48 g of3-hydroxypyridine (5.0 mmol) in 2 mL of DMF at room temperature, and themixture was stirred for an hour. The resulting brown solution wasice-cooled, 0.81 mL of tert-butyl bromoacetate (5.5 mmol) was added, andthe mixture was stirred under ice-cooling for an hour followed bystirring at room temperature for 2 hours. After addition of water, themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried and evaporated. The residue was purified bycolumn chromatography on silica gel (eluent: chloroform:ethylacetate=5:1), to give 0.34 g of tert-butyl 3-pyridyloxyacetate (Yield:32.5%) as a clear oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.49 (9H, s), 4.56 (2H, s), 7.18-7.24(2H, m), 8.26 (1H, dd, J=1.5, 3.6 Hz), 8.32 (1H, d, J=2.9 Hz).

(46-2) To a solution of 0.14 g of the compound from the process (46-1)(0.67 mmol) in 2 mL of dichloromethane was added 2 mL of trifluoroaceticacid, and the solution was stirred at room temperature for 3 hours.After evaporation, diisopropyl ether was added, and the precipitatedsolid was collected by filtration and dried to give 0.15 g of3-pyridyloxyacetic acid trifluoroacetate (Yield: 83.8%) as a lightyellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.86 (2H, s), 7.57 (1H, dd, J=4.4, 8.1Hz), 7.67 (1H, ddd, J=1.5, 1.5, 8.8 Hz), 8.31 (1H, d, J=5.1 Hz), 8.46(1H, d, J=2.1 Hz), 13.00 (1H, br.s).

(46-3) To a suspension of 100 mg of the compound from the process (46-2)(0.37 mmol) and 255 mg of the compound from Example 1, the process (1-4)(0.75 mmol) in 5 mL of dichloromethane was added 0.14 mL oftriethylamine (1.0 mmol), and the mixture was cooled with ice. Underice-cooling, to the mixture was added a solution of 140 mg of2-chloro-1,3-dimethylimidazolinium chloride (0.83 mmol) in 6 mL ofdichloromethane, and the mixture was warmed to room temperature withstirring for 7 hours, and left at room temperature overnight. Afteradding water and saturated brine, the mixture was extracted withchloroform.

The organic layer was washed with saturated brine, dried and evaporated.The residue was purified by column chromatography on silica gel(eluent:ethyl acetate:methanol=10:1) to give 0.37 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide(Yield: quantitative) as a clear oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.52 (9H, s), 4.62 (2H, s), 4.63 (2H, d,J=7.3 Hz), 6.76 (1H, br.s), 6.90-7.00 (1H, br.s), 7.15-7.35 (5H, m),7.40 (2H, d, J=8.1 Hz), 7.82 (1H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz),8.32 (1H, dd, J=2.1, 4.4 Hz), 8.37 (1H, d, J=2.8 Hz), 9.20 (1H, br.s).

(46-4) To a solution of 175 mg of the compound from the process (46-3)(0.37 mmol) in 2 mL of dioxane and 2 mL of methanol was added 2 mL of 4Nhydrochloric acid-dioxane, and the mixture was stirred at roomtemperature for 2 hours. After adding saturated sodium bicarbonate aq.,the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried and evaporated. To the residue wasadded methanol and diisopropyl ether, and the precipitated solid wascollected by filtration and dried to give 90 mg ofN-(2-aminophenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide(Yield: 64.6%) as an opalescent solid.

mp: 154-155° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.42 (2H, d, J=5.9Hz), 4.69 (2H, s), 4.89 (2H, br.s), 6.59 (1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97 (1H, dd, J=6.6, 7.3 Hz), 7.16 (1H, d, J=7.3 Hz),7.33-7.39 (4H, m), 7.92 (2H, d, J=8.1 Hz), 8.21 (1H, dd, J=1.5, 4.4 Hz),8.35 (1H, d, J=2.9 Hz), 8.80 (1H, br.t, J=5.9 Hz), 9.63 (1H, br.s); IR(KBr)cm⁻¹: 3307, 1672, 1631, 1523, 1456, 1429, 1269, 1231, 803, 756.

Example 47 Preparation ofN-(2-Aminophenyl)-4-[N-[2-(pyridin-3-yl)oxy]propionylaminomethyl]benzamide(Table 4: Compound 3)

(47-1) To a suspension of 1.20 g of sodium hydride (60% oil dispersion;30.0 mmol) in 10 mL of dry DMF at room temperature were added dropwise2.85 g of 3-hydroxypyridine (30 mmol) in 10 mL of dry DMF, maintainingthe temperature below 40° C., and the mixture was stirred at roomtemperature for 90 min. Under ice-cooling, 6.28 g of tert-butyl2-bromopropionate (30 mmol) in 10 mL of dry DMF were slowly addeddropwise, maintaining the inner temperature within 5 to 10° C., and thenthe mixture was warmed to room temperature with stirring for 4 hours.After neutralizing with saturated sodium bicarbonate aq., the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and then saturated brine, dried and evaporated. The residue waspurified by column chromatography on silica gel (eluent: n-hexane:ethylacetate=2:1) to give 4.15 g of tert-butyl 2-(pyridin-3-yl)oxypropionate(Yield: 62%) as a brown oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.44 (9H, s), 1.61 (3H, d, J=7.3 Hz),4.66 (1H, q, J=7.3 Hz), 7.13-7.23 (2H, m), 8.24 (1H, dd, J=1.5, 4.4 Hz),8.29 (1H, d, J=2.1 Hz).

(47-2) To a solution of 1.65 g of the compound from the process (47-1)(7.4 mmol) in 9 mL of dichloromethane was added 9 mL of trifluoroaceticacid, maintaining the temperature below 30° C., and then the mixture wasstirred at room temperature for 8 hours. After evaporation, diisopropylether was added and the precipitated solid was collected by filtrationand dried to give 1.86 g of 2-(pyridin-3-yl)oxypropionic acidtrifluoroacetate (Yield 43.5%) as a light brown solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.53 (3H, d, J=6.6 Hz), 5.12 (1H, q,J=6.6 Hz), 7.60-7.75 (2H, m), 8.35 (1H, d, J=5.1 Hz), 8.47 (1H, s), 12.9(1H, br.s).

(47-3) To a suspension of 0.98 g of the compound from the process (47-2)(3.5 mmol) and 1.02 g of the compound from Example 1, the process (1-4)(3.0 mmol) in 20 mL of dichloromethane was added 1.3 mL of triethylamine(9.0 mmol) and then the mixture was ice-cooled. Under ice-cooling, 0.59g of 2-chloro-1,3-dimethylimidazolinium chloride (3.5 mmol) in 5 mL ofdichloromethane was added dropwise, and the mixture was stirred foradditional 2 hours. The mixture was neutralized with saturated sodiumbicarbonate aq., and then extracted with chloroform. The organic layerwas washed with saturated brine, dried and evaporated. The residue waspurified by column chromatography on silica gel (eluent: ethylacetate:methanol=10:1) to give 1.64 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-[N-[2-(pyridin-3-yl)oxypropionyl]aminomethyl]benzamideas a mixture with 1,3-dimethyl-2-imidazolinone.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 1.64 (3H, d, J=7.3 Hz),4.54 (2H, m), 4.78 (1H, q, J=6.6 Hz), 6.87 (2H, br.s), 7.13-7.30 (6H, m)7.81 (1H, d, J=7.3 Hz), 7.90 (2H, d, J=8.1 Hz), 8.29 (1H, dd, J=1.5, 4.4Hz), 8.33 (1H, d, J=2.1 Hz), 9.22 (1H, br.s).

(47-4) The compound from the process (47-3) (1.64 g) was dissolved in 10mL of dioxane and 4 mL of methanol. To the solution was added 10 mL of4N hydrochloric acid-dioxane solution at room temperature, and themixture was stirred for 2 hours. The mixture was neutralized withsaturated sodium bicarbonate aq. and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and evaporated. Tothe residue were added methanol and diisopropyl ether, and theprecipitated solid was collected by filtration and dried to give 0.71 gofN-(2-aminophenyl)-4-[N-[2-(pyridin-3-yl)oxy]propionylaminomethyl]benzamide(Yield: 60.5% for the 2 steps) as a white solid.

mp: 171-173° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.51 (3H, d,J=6.6 Hz), 4.36 (2H, d, J=5.9 Hz), 4.89 (2H, br.s), 4.90 (1H, t, J=6.6Hz), 6.60 (1H, dd, J=6.6, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd,J=6.6, 7.3 Hz), 7.15 (1H, d, J=7.3 Hz), 7.27 (2H, d, J=8.1 Hz),7.33-7.37 (2H, m), 7.89 (2H, d, J=8.1 Hz), 8.21 (1H, dd, J=2.9, 2.9 Hz),8.32 (1H, d, J=1.5 Hz), 8.82 (1H, t, J=5.9 Hz), 9.63 (1H, br.s).

Example 48 Preparation ofN-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 82)

(48-1) To a solution of 384 mg of 3-pyridinemethanol (3.52 mmol) in 5 mLof dry THF were added 523 mg of N,N′-carbonyldiimidazole (3.22 mmol) atroom temperature. After stirring for an hour, to the mixture was added1.0 g of the compound from Example 1, the process (1-4) (2.93 mmol) in 6mL of dry THF.

After being left at room temperature overnight, to the mixture was added100 mL of chloroform, and the mixture was washed with water (3×20 mL)and then saturated brine, and dried over anhydrous magnesium sulfate.After evaporating the solvent under reduced pressure, the residue waspurified by column chromatography on silica gel (eluent:chloroform:methanol=30:1) to give 1.27 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Yield: quantitative) as an amorphous solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 4.45 (2H, d, J=5.9 Hz),5.16 (1H, s), 7.10-7.50 (7H, m), 7.70 (1H, d, J=8.1 Hz), 7.80 (1H, d,J=7.3 Hz), 7.93 (1H, d, J=8.1 Hz), 8.57 (1H, d, J=4.4 Hz), 8.63 (1H, s),9.17 (1H, s).

(48-2) The compound from the process (48-1) (1.2 g, 2.8 mmol) wasdissolved in 10 mL of methanol. To the solution was added 20 mL of4N-hydrochloric acid-dioxane. The mixture was stirred at roomtemperature for 1.5 hours, and then poured into diluted sodium hydroxideaq. and extracted with chloroform (3×60 mL). The combined organic layerwas washed twice with saturated brine, dried over anhydrous magnesiumsulfate and concentrated to give 0.88 g of crystals, which were thenrecrystallized from 16 mL of ethanol, to give 668 mg ofN-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Yield: 73%).

mp: 159-160° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=5.9Hz), 4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J=7.3 Hz), 6.78 (1H, d,J=7 Hz), 6.97 (1H, t, J=7 Hz), 7.17 (1H, d, J=8 Hz), 7.30-7.50 (3H, m),7.78 (1H, d, J=8 Hz), 7.93 (2H, d, J=8 Hz), 8.53 (1H, d, J=3.7 Hz), 8.59(1H, s), 9.61 (1H, s). IR (KBr)cm⁻¹: 3295, 1648, 1541, 1508, 1457, 1309,1183, 742.

As described in Example 48, the compounds of Examples 49 to 87 wereprepared, each of whose melting point (mp), ¹H NMR data and/or IR dataare shown below.

Example 49N-(2-Aminophenyl)-4-[N-(benzyloxycarbonyl)aminomethyl]benzamide (Table1: Compound 11)

mp: 174-178° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=5.9Hz), 4.89 (2H, br.s), 5.06 (2H, s), 6.59 (1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=7.3 Hz),7.30-7.40 (6H, m), 7.93 (3H, m), 9.63 (1H, s). IR (KBr)cm⁻¹: 3332, 1687,1652, 1536, 1456, 1279, 747.

Example 50N-(2-Aminophenyl)-4-[N-(4-(imidazol-1-yl)benzyl)oxycarbonylaminomethyl]benzamide(Table 1: Compound 47)

mp: 195-198° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.29 (2H, d, J=6.6Hz), 4.88 (2H, s), 5.10 (2H, s), 6.60-6.63 (1H, m), 6.78 (1H, d, J=8.1Hz), 6.97 (1H, t, J=7.3 Hz), 7.11 (1H, s), 7.16 (1H, d, J=7.3 Hz), 7.37(2H, d, J=8.1 Hz), 7.49 (2H, d, J=8.8 Hz), 7.66 (2H, d, J=8.1 Hz), 7.74(1H, s), 7.92-7.96 (3H, m), 8.25 (1H, s), 9.62 (1H, s).

Example 51N-(2-Aminophenyl)-4-[N-(pyridin-2-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 171)

mp: 166-167° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.30 (2H, d, J=5.9Hz), 4.88 (2H, br.s), 5.12 (2H, s), 6.60 (1H, dd, J=7.3, 8.1 Hz) 6.78(1H, d, J=8.1 Hz), 6.97 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16 (1H, d,J=7.3 Hz), 7.33 (1H, dd, J=3.7, 7.3 Hz), 7.40 (3H, d, J=8.1 Hz), 7.83(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.94 (2H, d, J=8.1 Hz), 8.03 (1H, t,J=5.9 Hz), 8.55 (1H, d, J=5.1 Hz), 9.62 (1H, br.s); IR (KBr)cm⁻¹: 3334,1694, 1632, 1580, 1276, 755.

Example 52N-(2-Aminophenyl)-4-[N-[2-(pyridin-2-yl)ethoxycarbonyl]aminomethyl]benzamide(Table 1: Compound 172)

mp: 146-148° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.04 (2H, t, J=6.6Hz), 4.23 (2H, d, J=5.9 Hz), 4.36 (2H, t, J=6.6 Hz), 4.88 (2H, br.s),6.60 (1H, dd, J=7.3, 8.1 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd,J=7.3, 8.1 Hz), 7.15-7.30 (3H, m), 7.34 (2H, d, J=8.1 Hz), 7.69-7.77(2H, m), 7.92 (2H, d, J=7.3 Hz), 8.50 (1H, d, J=4.4 Hz), 9.62 (1H,br.s); IR (KBr)cm⁻¹: 3330, 1690, 1633, 1594, 1524, 1277, 760.

Example 53N-(2-Aminophenyl)-4-[N-(6-methylpyridin-2-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 179)

mp: 138° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.47 (3H, s), 4.30 (2H, d,J=5.9 Hz), 5.07 (4H, s), 6.63 (1H, t, J=8.1 Hz), 6.80 (1H, d, J=7.34),6.98 (1H, t, J=8.1 Hz), 7.18 (3H, d, J=7.3 Hz), 7.40 (2H, d, J=8.1 Hz),7.71 (1H, t, J=8.1 Hz), 7.94 (2H, d, J=8.1 Hz), 8.03 (1H, t, J=5.9 Hz),9.66 (1H, s); IR (KBr)cm⁻¹: 3335, 1693, 1634, 1259.

Example 54N-(2-Aminophenyl)-4-[N-[2-(pyridin-3-yl)ethoxycarbonyl]aminomethyl]benzamide(Table 1: Compound 83)

mp: 120-125° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.91 (2H, t, J=6.6Hz), 4.22 (4H, t, J=6.6 Hz), 4.89 (2H, s), 6.55-6.63 (1H, m), 6.78 (1H,dd, J=8.1, 1.5 Hz), 6.97 (1H, t, J=6.6 Hz), 7.17 (1H, d, J=6.6 Hz), 7.33(3H, d, J=8.1 Hz), 7.69 (1H, d, J=8.1 Hz), 7.79 (1H, t, J=6.6 Hz), 7.93(2H, d, J=8.0 Hz), 8.43-8.49 (2H, m), 9.62 (1H, s); IR (KBr)cm⁻¹: 3234,1705, 1655, 1260.

Example 55N-(2-Aminophenyl)-4-[N-[3-(pyridin-3-yl)propyloxycarbonyl]aminomethyl]benzamide(Table 1: Compound 84)

mp: 121-124° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.83-1.94 (2H, m),2.67 (2H, t, J=7.3 Hz), 3.98 (2H, t, J=6.6 Hz), 4.26 (2H, d, J=5.9 Hz),4.89 (2H, br.s), 6.60 (1H, dd, J=8.1, 8.1 Hz), 6.78 (1H, d, J=7.3 Hz),6.97 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16 (1H, d, J=8.1 Hz), 7.29-7.33(1H, m), 7.37 (1H, d, J=8.1 Hz), 7.64 (1H, d, J=8.1 Hz), 7.81 (1H, dd,J=5.9, 6.6 Hz), 7.94 (2H, d, J=8.1 Hz), 8.40-8.44 (2H, m), 9.63 (1H,br.s); IR (KBr)cm⁻¹: 3348, 1696, 1635, 1523, 1458, 1302, 1272, 1141,1019, 754, 713.

Example 56N-(2-Aminophenyl)-4-[N-(2-methylpyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 142)

mp: 164-165° C.; ¹H NMR (270 MHz, DMSO-d₆) ppm: 2.49 (3H, s), 4.28 (2H,d, J=6.6 Hz), 4.89 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J=6.6 Hz), 6.78(1H, d, J=8.1 Hz), 6.90 (1H, t, J=7.3 Hz), 7.17 (1H, d, J=7.3 Hz),7.21-7.26 (1H, m), 7.37 (2H, d, J=8.1 Hz), 7.68 (1H, d, J=6.6 Hz),7.92-8.00 (3H, m), 8.39 (1H, d, J=4.4 Hz), 9.62 (1H, s); IR (KBr)cm⁻¹:3332, 1719, 1630, 1260.

Example 57N-(2-Aminophenyl)-4-[N-(6-methylpyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 144)

mp: 164-165° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.46 (3H, s), 4.27(2H, d, J=6.6 Hz), 4.88 (2H, s), 5.05 (2H, s), 6.59 (1H, dt, J=1.5, 8.1Hz), 6.78 (1H, dd, J=1.5, 8.1 Hz), 6.97 (1H, dt, J=1.5, 7.3 Hz), 7.17(1H, d, J=7.3 Hz), 7.26 (1H, d, J=8.1 Hz), 7.36 (2H, d, J=8.1 Hz), 7.67(1H, dd, J=2.2, 8.1 Hz), 7.93 (3H, d, J=8.1 Hz), 8.45 (1H, d, J=1.5 Hz),9.62 (1H, s); IR (KBr)cm⁻¹: 3293, 1701, 1632, 1260.

Example 58N-(2-Aminophenyl)-4-[N-(2-chloropyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 155)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) ppm: 4.30 (2H, d, J=5.9 Hz),5.00 (2H, s), 5.13 (2H, s), 6.61 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=1.5,8.1 Hz), 6.98 (1H, dt, J=1.5, 7.3 Hz), 7.17 (1H, d, J=6.6 Hz), 7.39 (2H,d, J=8.8 Hz), 7.47-7.52 (1H, m), 7.91-7.96 (3H, m), 8.08 (1H, t, J=5.9Hz), 8.40 (1H, dd, J=4.4, 1.5 Hz), 9.64 (1H, s); IR (KBr)cm⁻¹: 3340,1702, 1632, 1273.

Example 59N-(2-Aminophenyl)-4-[N-(6-chloropyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 157)

mp: 180-185° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.24 (2H, d, J=5.9Hz), 4.89 (2H, br.s), 5.10 (2H, s), 6.60 (1H, t, J=7.3 Hz), 6.78 (1H, d,J=8.1 Hz), 6.97 (1H, dt, J=1.5, 8.1 Hz), 7.16 (1H, d, J=6.6 Hz), 7.37(2H, d, J=8.1 Hz), 7.56 (1H, d, J=8.1 Hz), 7.85-8.02 (4H, m), 8.44 (1H,d, J=2.2 Hz), 9.62 (1H, s); IR (KBr)cm⁻¹: 3346, 3282, 1696, 1533, 1271.

Example 60N-(2-Aminophenyl)-4-[N-(pyridin-4-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 181)

mp: 180-183° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.30 (2H, d, J=6.6Hz), 4.89 (2H, s), 5.12 (2H, s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H,dd, J=1.5, 7.3 Hz), 6.97 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16 (1H, d,J=7.3 Hz), 7.34 (2H, d, J=5.9 Hz), 7.39 (2H, d, J=8.1 Hz), 7.94 (2H, d,J=8.1 Hz), 8.09 (1H, t, J=5.9 Hz), 8.57 (1H, d), 9.64 (1H, br.s); IR(KBr)cm⁻¹: 3394, 3290, 1711, 1645, 1624, 1535, 1504, 1321, 1251, 1138,1049, 763.

Example 61N-(2-Aminophenyl)-4-[N-[2-(thiophen-3-yl)ethoxycarbonyl]aminomethyl]benzamide(Table 1: Compound 203)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.90 (2H, t, J=7.3Hz), 4.17-4.26 (4H, m), 4.89 (2H, s), 6.60 (1H, t, J=8.1 Hz), 6.78 (1H,d, J=6.6 Hz), 6.97 (1H, t, J=7.3 Hz), 7.06 (1H, d, J=5.1 Hz), 7.17 (1H,d, J=7.3 Hz), 7.26 (1H, s), 7.36 (2H, d, J=8.1 Hz), 7.47 (1H, t, J=2.2Hz), 7.81 (1H, t, J=5.9 Hz), 7.93 (2H, d, J=8.1 Hz), 9.63 (1H, s); IR(KBr)cm⁻¹: 3314, 1716, 1638, 1252.

Example 62N-(2-Aminophenyl)-4-[N-(3-phenyloxazol-5-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 211)

mp: 192-195° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.30 (2H, d, J=5.9Hz), 4.89 (2H, s), 5.25 (2H, s), 6.60 (1H, t, J=6.6 Hz), 6.68 (1H, d,J=8.1 Hz), 6.94 (1H, t, J=7.3 Hz), 7.09 (1H, s), 7.16 (1H, d, J=7.3 Hz),7.39 (2H, d, J=8.1 Hz), 7.51 (4H, d, J=2.2 Hz), 7.87-7.96 (5H, m), 8.12(1H, t, J=5.9 Hz), 9.63 (1H, s); IR (KBr)cm⁻¹: 3292, 1718, 1630, 1262.

Example 63N-(2-Aminophenyl)-4-[N-(thiazol-5-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 216)

mp: 168-175° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=5.9Hz), 4.91 (2H, br.s), 5.30 (2H, s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=7.3 Hz),7.36 (2H, d, J=8.1 Hz), 7.91-8.00 (4H, m), 9.09 (1H, s), 9.63 (1H, s);IR (KBr)cm⁻¹: 3346 (br.), 1697, 1636, 1525, 1456, 1271, 873, 753.

Example 64N-(2-Aminophenyl)-4-[N-[2-(4-methylthiazol-5-yl)ethoxycarbonyl]aminomethyl]benzamide(Table 1: Compound 217)

mp: 130-133° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.32 (3H, s), 3.07(2H, t, J=5.9 Hz), 4.15 (2H, t, J=5.9 Hz), 4.25 (2H, d, J=6.6 Hz), 4.89(2H, s), 6.60 (1H, t, J=5.9 Hz), 6.78 (1H, dd, J=7.3, 1.5 Hz), 6.97 (1H,dt, J=1.5, 7.3 Hz), 7.16 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=8.1 Hz), 7.83(1H, t, J=5.9 Hz), 7.94 (2H, d, J=8.1 Hz), 8.85 (1H, s), 9.62 (1H, s);IR (KBr)cm⁻¹: 3350, 1691, 1635, 1270.

Example 65N-(2-Aminophenyl)-4-[N-(1-methylpiperidin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 225)

mp: 130-135° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.49-1.78 (3H, m),1.83-2.01 (3H, m), 2.30 (3H, s), 2.85 (2H, t), 3.74-3.94 (2H, m), 4.25(2H, d, J=5.8 Hz), 6.55-6.62 (3H, m), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H,t, J=7.3 Hz), 7.16 (1H, d, J=8.1 Hz), 7.37 (2H, d, J=8.1 Hz), 7.79 (1H,t, J=6.6 Hz), 7.93 (2H, d, J=8.0 Hz), 9.66 (1H, s); IR (KBr)cm⁻¹: 3323,2722, 1702, 1648, 1263.

Example 66N-(2-Aminophenyl)-4-[N-(4-methylpiperazin-1-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 227)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.73 (2H, t, J=6.6Hz), 2.36-2.63 (13H, m), 4.00 (2H, t, J=6.6 Hz), 4.30 (2H, d, J=5.8 Hz),6.55-6.63 (4H, m), 6.78 (1H, d, J=6.6 Hz), 6.97 (1H, t, J=7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.37 (2H, d, J=8.7 Hz), 7.73 (1H, t, J=5.9 Hz), 7.94(2H, d, J=8.0 Hz), 9.66 (1H, s); IR (KBr)cm⁻¹: 3341, 2706, 1701, 1262.

Example 67N-(2-Aminophenyl)-4-[N-(tetrahydrofuran-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 221)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.50-1.60 (1H, m),1.88-2.00 (1H, m), 2.44-2.54 (1H, m), 3.41-3.47 (1H, m), 3.56-3.77 (3H,m), 3.85-4.04 (2H, m), 4.25 (2H, d, J=5.9 Hz), 4.89 (2H, s), 6.60 (1H,dd, J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1Hz), 7.17 (1H, d, J=8.1 Hz), 7.37 (2H, d, J=8.1 Hz), 7.81 (1H, t, J=5.9Hz), 7.94 (2H, d, J=8.1 Hz), 9.62 (1H, br.s); IR (KBr)cm⁻¹: 3349, 1695,1635, 1523, 1457, 1259, 754.

Example 68 N-(2-Aminophenyl)-4-[N-(phenoxycarbonyl)aminomethyl]benzamide(Table 1: Compound 12)

mp: 174-175° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.36 (2H, d, J=5.9Hz), 4.90 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz, 6.77 (1H, dd, J=7.3,7.3 Hz), 6.98 (1H, ddd, J=1.5, 7.3, 7.3 Hz), 7.05-7.24 (4H, m),7.39-7.46 (4H, m), 7.97 (2H, d, J=8.1 Hz), 8.41 (1H, t, J=5.9 Hz), 9.65(1H, br.s); IR (KBr)cm⁻¹: 3443, 3362, 3313, 1732, 1706, 1636, 1527,1493, 1458, 1305, 1217, 748.

Example 69N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)oxycarbonylaminomethyl]benzamide(Table 1: Compound 81)

mp: 209° C.(dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.38 (2H, d, J=6.6Hz), 4.90 (2H, br.s), 6.55-6.63 (1H, m), 6.78 (1H, d, J=8.1 Hz), 7.00(1H, dd, J=7.3, 7.3 Hz), 7.17 (1H, d, J=8.8 Hz), 7.37-7.47 (3H, m), 7.64(1H, d, J=8.8 Hz), 7.97 (2H, d, J=8.1 Hz), 8.43 (2H, d, J=3.1 Hz); 8.59(1H, t, J=5.9 Hz), 9.66 (1H, br.s).

Example 70N-(2-Amino-5-fluorophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 110)

mp: 160-162° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=6.6Hz), 4.81 (2H, s), 5.10 (2H, s), 6.70-6.90 (2H, m), 7.10-8.00 (8H, m),8.53 (1H, d, J=3.6 Hz), 8.59 (1H, s), 9.61 (1H, s); IR (KBr)cm⁻¹: 3269,1716, 1638, 1488, 1436, 1247, 1141, 1043, 744.

Example 71N-(2-Aminophenyl)-4-[N-(2-aminophenyl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 51)

mp: 149-151° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d,J=5.9 Hz), 4.88 (2H, s), 4.96 (2H, s), 5.06 (2H, s), 6.53 (1H, dd,J=7.3, 7.3 Hz), 6.56-6.67 (2H, m), 6.78 (1H, dd, J=1.5, 8.1 Hz),6.93-7.12 (3H, m), 7.16 (1H, d, J=6.6 Hz), 7.38 (2H, d, J=8.1 Hz), 7.86(1H, t-like, J=5.9 Hz), 7.93 (2H, d, J=8.1 Hz), 9.61 (1H, s); IR(KBr)cm⁻¹: 3336, 1685, 1632, 1527, 1276, 748.

Example 72N-(2-Aminophenyl)-4-[N-(quinuclidin-3-yl)oxycarbonylaminomethyl]benzamide(Table 1: Compound 228)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.30-1.90 (4H, m),1.90 (1H, br.s), 2.45-2.80 (6H, m), 3.04-3.13 (1H, m), 4.15 (2H, d,J=5.9 Hz), 4.55-4.60 (1H, m), 4.88 (2H, br.s), 6.60 (1H, ddd, J=1.5,7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, ddd, J=1.5, 7.3, 7.3Hz), 7.17 (1H, d, J=6.6 Hz), 7.37 (2H, d, J=8.1 Hz), 7.78 (1H, t, J=5.9Hz), 7.94 (1H, d, J=7.3 Hz), 9.62 (1H, s); IR (KBr)cm⁻¹: 3328, 2942,1700, 1648, 1504, 1259, 749.

Example 73N-(2-Aminophenyl)-4-[N-(3-aminophenyl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 52)

mp: 149-153° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.27 (2H, d,J=5.9 Hz), 4.88 and 4.89 (total 4H, each br.s), 5.08 (2H, s), 6.47-6.63(3H, m), 6.78 (1H, d, J=8.1 Hz), 6.94-7.02 (2H, m) 7.15 (1H, dd, J=7.3,8.8 Hz), 7.37 (2H, d, J=8.1 Hz), 7.84 (1H, t, J=5.9 Hz), 7.93 (2H, d,J=8.8 Hz), 9.61 (1H, br.s); IR (KBr)cm⁻¹: 3367, 1682, 1632, 1523, 1457,1261, 754.

Example 74N-(2-Aminophenyl)-4-[N-(1-methylimidazol-5-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 218)

mp: 162-165° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.62 (3H, s),4.27 (2H, d, J=5.9 Hz), 4.91 (2H, br.s), 5.05 (2H, s), 6.60 (1H, dd,J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.95-7.00 (2H, m), 7.16 (1H, d,J=7.3 Hz), 7.36 (2H, d, J=8.1 Hz), 7.63 (1H, s), 7.87-7.95 (3H, m), 9.64(1H, br.s); IR (KBr)cm⁻¹: 3293, 1688, 1651, 1534, 1506, 1259, 1121,1043, 748.

Example 75N-(2-Amino-4-chlorophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 113)

mp: 167-170° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=5.9Hz), 5.10 (2H, s), 5.21 (2H, s), 6.72 (1H, dd, J=2.2, 8.1 Hz), 6.81 (1H,d, J=2.2 Hz), 7.16 (1H, d, J=8.1 Hz), 7.37 (2H, d, J=8.1 Hz), 7.78 (1H,d, J=8.1 Hz), 7.92 (2H, d, J=8.1 Hz), 8.53 (1H, d, J=4.4 Hz), 8.59 (1H,s), 9.60 (1H, s); IR (KBr)cm⁻¹: 3347, 3062, 2931, 1653, 1576, 1505,1456, 1428, 1301, 1232, 1114, 1070, 1019.

Example 76N-(2-Aminophenyl)-4-[N-(5-methoxypridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 161)

mp: 169-170° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.83 (3H, s), 4.29(2H, d, J=6.6 Hz), 4.87 (2H, s), 5.09 (2H, s), 6.57-6.62 (1H, m),6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.14-7.18 (1H, m), 7.36-7.39 (3H,m), 7.91-7.99 (3H, m), 8.19-8.30 (2H, m), 9.63 (1H, s); IR (KBr)cm⁻¹:3330, 1694, 1633, 1524, 1457, 1298, 1269, 1045, 760.

Example 77N-(2-Aminophenyl)-4-[N-(pyrazin-2-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 192)

mp: 182° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.30 (2H, d, J=6.6 Hz),4.88 (2H, br.s), 5.20 (2H, s), 6.60 (1H, dd, J=7.3, 8.1 Hz), 6.78 (1H,d, J=8.1 Hz), 6.97 (1H, dd, J=6.6, 8.1 Hz), 7.16 (1H, d, J=7.3 Hz), 7.39(2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.08 (1H, t-like, J=6.6 Hz),8.61 (1H, s), 8.65 (1H, s), 8.68 (1H, s), 9.63 (1H, s); IR (KBr)cm⁻¹:3266, 1709, 1632, 1535, 1508, 1284, 1055, 1022, 744.

Example 78N-(2-Amino-5-methoxyphenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 121)

mp: 141-143° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.66 (3H, s), 4.29(2H, d, J=5.9 Hz), 4.51 (2H, br.s), 5.10 (2H, s), 6.63 (1H, dd, J=2.9,8.8 Hz), 6.74 (1H, d, J=8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 7.38 (2H, d,J=8.8 Hz), 7.41 (1H, s), 7.79 (1H, d, J=8.1 Hz), 7.92 (2H, d, J=8.1 Hz),7.98 (1H, t, J=5.9 Hz), 8.54 (1H, d, J=3.7 Hz), 8.60 (1H, s), 9.65 (1H,s).

Example 79N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methyl-N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 109)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.50 (2H, s), 4.56(2H, s), 4.87 (2H, s ), 5.21 (2H, s), 6.60 (1H, t, J=7.7 Hz), 6.78 (1H,d, J=7.3 Hz), 6.97 (1H, d, J=7.3 Hz), 7.17 (1H, d, J=7.3 Hz), 7.20-7.5.0(4H, m), 7.60-8.00 (4H, m), 8.40-8.60 (4H, m), 9.65 (1H, s); IR(KBr)cm⁻¹: 3268, 1700, 1504, 1246, 1120, 940, 714.

Example 80N-(2-Aminophenyl)-4-[N-[3-(pyridin-3-yl)propyl]-N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 120)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.75-1.90 (2H, m),2.48-2.62 (2H, m), 3.20-3.36 (2H, m), 4.55 (2H, s), 4.89 (2H, s), 5.16(2H, s), 6.57-6.63 (1H, m), 6.76-6.80 (1H, m), 6.94-6.99 (1H, m),7.14-7.17 (1H, m), 7.32-7.74 (6H, m), 7.94 (2H, d, J=8.1 Hz), 8.30-8.65(4H, m), 9.64 (1H, s).

Example 81N-(2-Hydroxyphenyl)-4-[N-(pyridin-3-yl)methyl-N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 115)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.52 (2H, s), 4.57(2H, s), 5.20 (2H, s ), 6.84 (1H, t, J=6.6 Hz), 6.93 (1H, d, J=6.6 Hz),7.03 (1H, d, J=7.3 Hz), 7.37 (4H, m), 7.68 (2H, dd, J=1.5, 8.1 Hz), 7.92(2H, br.s), 8.53 (4H, m), 9.49 (1H, s ), 9.77 (1H, br.s); IR (KBr)cm⁻¹:3035, 1698, 1243, 1118, 754, 640.

Example 82N-(2-Hydroxyphenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 111)

mp: 162-164° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.29 (1H, d, J=5.9Hz), 5.10 (2H, s), 6.83 (1H, t, J=8.1 Hz), 6.92 (1H, d, J=6.6 Hz), 7.07(1H, t, J=6.6 Hz), 7.39 (2H, d, J=8.8 Hz), 7.43 (1H, d, J=5.1 Hz), 7.68(2H, d, J=8.1 Hz), 7.80 (1H, d, J=8.1 Hz), 7.92 (2H, d, J=8.1 Hz), 7.99(1H, t, J=5.9 Hz), 8.54 (1H, d, J=4.4 Hz), 8.60 (1H, s), 9.49 (1H, s),9.76 (1H, br.s); IR (KBr)cm⁻¹: 3333, 3259, 1694, 1645, 1529, 1267, 720.

Example 83N-(2,4-Dihydroxyphenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 116)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.27 (2H, d, J=6.6Hz), 5.10 (2H, s), 6.20 (2H, dd, J=2.2, 8.1 Hz), 6.39 (2H, d, J=2.9 Hz),6.88 (2H, d, J=8.8 Hz), 7.33 (1H, d, J=8.1 Hz), 7.41 (1H, dd, J=5.1, 7.1Hz), 7.89 (1H, d, J=8.8 Hz), 7.98 (1H, t, J=6.6 Hz), 8.05 (2H, s), 8.52(1H, m), 8.59 (1H, s), 9.30 (2H, br.s); IR (KBr)cm⁻¹: 3387, 1702, 1612,1311, 1169, 845.

Example 84N-(2-Hydroxy-5-methylphenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 118)

mp: 155-155.5° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.22 (3H, s), 4.29(2H, d, J=5.8 Hz), 5.11 (2H, s), 6.82 (2H, m), 7.39 (2H, d, J=8.8 Hz),7.42 (2H, m), 7.51 (1H, s), 7.79 (1H, d, J=8.1 Hz), 7.92 (1H, d, J=8.1Hz), 7.98 (1H, t, J=5.9 Hz), 8.54 (1H, d, J=4.4 Hz), 8.60 (1H, s), 9.48(2H, d, J=8.1 Hz); IR (KBr)cm⁻¹: 3306, 1723, 1655, 1525, 801, 639.

Example 85N-(2-Hydroxy-5-methoxyphenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide(Table 1: Compound 119)

mp: 175-176° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.69 (3H, s), 4.29(2H, d, J=5.9 Hz), 5.10 (2H, s), 6.63 (1H, dd, J=2.9, 8.7 Hz), 6.84 (1H,d, J=8.8 Hz), 7.41 (4H, m), 7.79 (1H, d, J=8.1 Hz), 7.91 (1H, d, J=8.1Hz), 7.99 (1H, t, J=5.9 Hz), 8.54 (1H, d, J=5.1 Hz), 8.60 (1H, s), 9.31(1H, s), 9.45 (1H, s); IR (KBr)cm⁻¹: 3305, 1687, 1573, 1262, 1039, 868.

Example 86N-(2-Aminophenyl)-4-[N-[2-(pyridin-3-yl)ethoxycarbonyl]amino]benzamide(Table 1: Compound 124)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.00 (2H, t, J=6.6Hz), 4.37 (2H, t, J=6.6 Hz), 4.87 (2H, br.s), 6.60 (1H, t, J=7.3 Hz),6.97 (1H, t, J=7.3 Hz) 7.15 (1H, d, J=7.3 Hz), 7.36 (1H, dd, J=4.4, 8.1Hz), 7.56 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.8 Hz), 8.46 (1H, d, J=4.4Hz), 8.54 (1H, d, J=2.2 Hz), 9.95 (1H, s); IR (KBr)cm⁻¹: 3285, 1695,1519, 1315, 1233, 1079.

Example 87N-(2-Aminophenyl)-5-[(pyridin-3-yl)methoxycarbonyl]aminobenzofuran-2-carboxyamide(Table 3: Compound 2)

mp: 173-174° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 5.22 (2H, s), 6.60(1H, dd, J=8.1, 8 Hz), 6.79 (1H, dd, J=1.5, 8.1 Hz), 7.00 (1H, dd,J=8.1, 8 Hz), 7.20 (1H, dd, J=1.5, 8.1 Hz), 7.44 (1H, m), 7.48 (1H, dd,J=1.5, 8.8 Hz), 7.61 (1H, d, J=8.8 Hz), 7.67 (1H, s), 7.88 (1H, dd,J=1.5, 8 Hz), 7.96 (1H, d, J=1.5 Hz), 8.56 (1H, dd, J=1.5, 4.8 Hz), 8.68(1H, d, J=1.5 Hz), 9.83 (1H, s), 9.91 (1H, s); IR (KBr)cm⁻¹: 3308, 1707,1667, 1584, 1536, 1452, 1316, 1248, 1157, 1128, 1070, 955, 879, 795,748, 710.

Example 88 Preparation ofN-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxythiocarbonylaminomethyl]benzamide(Table 1: Compound 86)

(88-1) To a solution of 20 mg of 3-pyridine methanol (0.18 mmol) in 5 mLof dry THF were added 30 mg of N,N′-thiocarbonyldiimidazole (0.16 mmol)at room temperature. After stirring overnight, to the mixture were added50 mg of the compound from Example 1, the process (1-4) (0.14 mmol).

After leaving at room temperature overnight, to the solution was added100 mL of chloroform, and the solution was washed with water (3×20 mL)and then saturated brine, and dried over anhydrous magnesium sulfate.After evaporation, the residue was purified by column chromatography onsilica gel (eluent: chloroform:methanol=30:1) to give 70 mg ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)methoxythiocarbonylaminomethyl]benzamide(Yield: 88%) as amorphous.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (9H, s), 4.73 (2H, d, J=5.9 Hz),5.52 (2H, s), 6.73-7.33 (3H, m), 7.35-7.43 (2H, m), 7.58-7.95 (5H, m),8.14-8.65 (3H, m), 9.80 (1H, s), 9.91 (1H, t).

(88-2) To a solution of 50 mg of the compound from the process (88-1)(0.10 mmol) in 3 mL of methanol was added 3 mL of 4N hydrochloricacid-dioxane, and the mixture was stirred at room temperature for 1.5hours. The mixture was poured into diluted sodium hydroxide aq. toneutralize the residual hydrochloric acid, and then was extracted withchloroform (3×10 mL). The organic layer was washed twice with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated to give34 mg ofN-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxythiocarbonylaminomethyl]benzamide(Yield: 87%).

mp: 154-156° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.73 (2H, d,J=5.9 Hz), 4.88 (2H, s), 5.52 (2H, s), 6.60 (1H, t, J=7.3 Hz), 6.77 (1H,d, J=8.1 Hz), 6.96 (1H, t, J=8.1 Hz), 7.16 (1H, d, J=7.3 Hz), 7.29-7.41(3H, m), 7.83-7.95 (3H, m), 8.50-8.56 (1H, m), 8.65 (1H, s), 9.62 (1H,s), 9.93 (1H, s); IR (KBr)cm⁻¹: 3204, 3035, 1631, 1523, 1456, 1289,1191, 920, 753.

Example 89 Preparation ofN-(2-Aminophenyl)-4-[N′-(pyridin-3-ylmethyl)ureidomethyl]benzamide(Table 1: Compound 88)

(89-1) To a solution of 0.28 g of 3-picolylamine (2.6 mmol) in 10 mL ofTHF was added 0.42 g of N,N′-carbonyldiimidazole (2.4 mmol) at roomtemperature, and the mixture was stirred for an hour. To the solutionwas added 0.58 g of the compound from Example 1, the process (1-4) (1.8mmol) at room temperature, and the solution was stirred for 3 hours andthen left overnight.

After diluting with water, the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried and evaporated.The residue was purified by column chromatography on silica gel (eluent:ethyl acetate:methanol=10:1) to give 0.77 g ofN-[2-(N-tert-butoxycarbonyl)amino]phenyl-4-[N′-(pyridin-3-ylmethyl)ureidomethyl]benzamide(Yield: 90%) as a white amorphous solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.46 (9H, s), 4.20 (2H, d, J=5.1 Hz),4.28 (2H, d, J=4.3 Hz), 6.10-6.30 (2H, m), 7.00-7.25 (4H, m), 7.33 (1H,d, J=7.3 Hz), 7.49-7.54 (2H, m), 7.58-7.64 (3H, m), 7.75 (1H, s), 8.28(1H, br.s), 8.39 (1H, d, J=5.1 Hz), 9.65 (1H, br.s).

(89-2) To a solution of 0.63 g of the compound from the process (89-1)(1.32 mmol) in 4 mL of dioxane and 2 mL of methanol was added 4 mL of 4Nhydrochloride-dioxane, and the mixture was stirred at room temperaturefor 2 hours. After adding saturated sodium bicarbonate aq., the mixturewas extracted with ethyl acetate-methyl ethyl ketone. The organic layerwas washed with saturated brine, dried and evaporated. The residue waswashed with diisopropyl ether to give 0.37 g ofN-(2-aminophenyl)-4-[N′-(pyridin-3-ylmethyl)ureidomethyl]benzamide(Yield: 74.7%) as a brown solid.

mp: 167-175° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.27 (2H, d, J=5.9Hz), 4.31 (2H, d, J=5.9 Hz), 4.89 (2H, br.s), 6.57-6.63 (3H, m), 6.78(1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.17 (1H, d, J=7.3 Hz),7.32-7.38 (3H, m), 7.66 (1H, d, J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz), 8.44(1H, d, J=5.1 Hz); IR (KBr)cm⁻¹: 3344, 3241, 1645, 1560, 1527, 1505,1283, 751, 708.

As described in Example 89, the compounds of Examples 90 to 95 wereprepared, each of whose melting point (mp), ¹H NMR data and/or IR dataare shown below.

Example 90 N-(2-Aminophenyl)-4-[N′-(3-aminophenyl)ureidomethyl]benzamide(Table 1: Compound 24)

mp: 206-208° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.35 (2H, d,J=5.9 Hz), 4.93 (4H, br.s), 6.13 (1H, d, J=7.3 Hz), 6.51-6.62 (3H, m),6.74-6.98 (3H, m), 7.12-7.18 (1H, m), 7.41 (2H, d, J=8.1 Hz), 7.94 (2H,d, J=8.1 Hz), 8.28 (1H, s), 9.61 (1H, s); IR (KBr)cm⁻¹: 3356, 3269,1640, 1555, 1495, 1458, 1308, 1236, 753.

Example 91 N-(2-Aminophenyl)-4-[N′-(pyridin-3-yl)ureidomethyl]benzamide(Table 1: Compound 87)

mp: 187-190° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.39 (2H, d, J=5.9Hz), 4.89 (2H, br.s), 6.59 (1H, d, J=77.3, 7.3 Hz), 6.77 (1H, d, J=6.6Hz), 6.88 (1H, t, J=5.9 Hz), 6.97 (1H, ddd, J=1.5, 6.6, 7.3 Hz), 7.16(1H, d, J=8.1 Hz), 7.26 (1H, dd, J=4.4, 8.1 Hz), 7.42 (2H, d, J=8.8 Hz),7.95 (2H, d, J=8.1 Hz), 7.89-7.96 (1H, m), 8.12 (1H, dd, J=1.5, 4.4 Hz),8.56 (1H, d, J=3.0 Hz), 8.85 (1H, s), 9.62 (1H, s); IR (KBr)cm⁻¹: 3248,1663, 1541, 1423, 1280, 1054.

Example 92N-(2-Aminophenyl)-4-[N′-(3-aminophenyl)thioureidomethyl]benzamide (Table1: Compound 25)

mp: 123° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.80 (2H, d, J=5.1Hz), 4.87 (2H, s), 5.12 (2H, s), 6.36 (1H, dd, J=1.5, 8.1 Hz), 6.48-6.63(3H, m), 6.78 (1H, d, J=6.6 Hz), 6.94-7.00 (2H, m), 7.17 (1H, d, J=8.1Hz), 7.42 (2H, d, J=8.1 Hz), 7.92-8.01 (3H, m), 9.46 (1H, s), 9.61 (1H,s); IR (KBr)cm⁻¹: 3335, 1616, 1528, 1503, 1456, 1311, 864, 751.

Example 93N-(2-Aminophenyl)-4-[N′-(3-nitrophenyl)thioureidomethyl]benzamide (Table1: Compound 20)

mp: 160° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.87 (2H, d, J=5.1Hz), 7.27-7.33 (3H, m), 7.46-7.63 (5H, m), 7.89-7.95 (2H, m), 8.05 (2H,d, J=8.1 Hz), 8.70 (1H, s), 8.84 (1H, t, J=8.9 Hz), 10.37 (1H, s).

Example 94N-(2-Amino-5-fluorophenyl)-4-[N′-(pyridin-3-yl)methylureidomethyl]benzamide(Table 1: Compound 112)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.77 (4H, d, J=5.1Hz), 4.85 (2H, s), 6.81 (2H, m), 7.16 (1H, dd, J=2.9, 10.3 Hz), 7.39(1H, dd, J=5.1, 8.1 Hz), 7.53 (2H, d, J=8.1 Hz), 7.81 (1H, d, J=8.1 Hz),7.93 (2H, d, J=8.1 Hz), 8.51 (1H, dd, J=1.5, 5.1 Hz), 8.62 (1H, d, J=1.5Hz), 9.66 (1H, s); IR (KBr)cm⁻¹: 3399, 1730, 1638, 1508, 1444, 1411.

Example 95N-(2-Hydroxyphenyl)-4-[N′-(pyridin-3-yl)methylureidomethyl]benzamide(Table 1: Compound 114)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.43 (2H, d, J=6.6Hz), 4.69 (2H, s), 6.83 (1H, t, J=6.6 Hz), 6.91 (1H, d, J=8.1 Hz), 7.68(1H, d, J=6.6 Hz), 7.82 (2H, d, J=88.1 Hz), 8.21 (1H, d, J=4.4 Hz), 8.35(1H, d, J=2.2 Hz), 8.81 (1H, t, J=6.6 Hz), 9.48 (1H, s), 9.75 (1H, s);IR (KBr)cm⁻¹: 3399, 1664, 1535, 1236, 1064.

Example 96 Preparation ofN-(2-Aminophenyl)-4-[2-[N-(pyridin-3-yl)acetylamino]ethyl]benzamide(Table 1: Compound 77)

(96-1) To a suspension of 3.40 g of terephthalaldehydic acid (22.6 mmol)in 25 mL of toluene was added 4 mL of thionyl chloride, and the mixturewas heated with stirring at 80° C. for 2 hours. After cooling andevaporation, the residue was dissolved in 50 mL of THF to give asolution of the acid chloride. To a solution of 4.16 g of the compoundfrom Example 1, the process (1-2) (20.0 mmol) in 10 mL of THF was added6 mL of triethylamine (42.8 mmol) and then the above solution of theacid chloride was added dropwise under ice-cooling over 30 min.

After stirring for 5 hours, to the mixture was added saturated sodiumbicarbonate aq., and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and evaporated. Theresidue was purified by column chromatography on silica gel (gradientelution with chloroform to chloroform:ethyl acetate=10:1) to give 3.42 gof N-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-formylbenzamide (Yield:50.2%) as a light brown solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.52 (9H, s), 6.77 (1H, br.s), 7.16-7.18(2H, m), 7.23-7.26 (1H, m), 7.88 (1H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8Hz), 8.13 (2H, d, J=8.8 Hz), 9.57 (1H, br.s), 10.11 (1H, br.s); IR(KBr)cm⁻¹: 3326, 3251, 1707, 1696, 1659, 1603, 1165.

(96-2) A suspension of 3.0 g of the compound from the process (96-1)(8.82 mmol) and 4.5 g of ethoxycarbonylmethyl triphenylphosphine (12.9mmol) in 10 mL of toluene was stirred in a stream of nitrogen at 80° C.for 5.5 hours. After cooling, the mixture was diluted with ethylacetate; washed with saturated sodium bicarbonate, water and saturatedbrine; dried; and evaporated. The residue was purified by columnchromatography on silica gel (eluent: chloroform:ethyl acetate=20:1) togive 3.3 g of ethyl4-[N-[2-[N-tert-butoxycarbonyl)aminophenyl]aminocarbonyl]cinnamate(Yield: 91.1%) as a yellow amorphous solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.35 (3H, t, J=7.3 Hz), 1.52 (9H, s),4.28 (2H, q, J=7.3 Hz), 6.52 (1H, d, J=15.1 Hz), 6.80 (1H, br.s),7.16-7.25 (3H, m), 7.61 (2H, d, J=8.1 Hz), 7.71 (1H, d, J=15.1 Hz), 7.82(1H, d, 7.3 Hz), 7.98 (2H, d, J=8.1 Hz), 9.34 (1H, br.s).

(96-3) To a solution of 2.50 g of the compound from the process (96-2)(6.09 mmol) in 30 mL of THF and 40 mL of methanol was added 10% Pd/C(wet, 0.5 g) in a stream of nitrogen, and then stirred in a stream ofhydrogen for 30 min. After filling with nitrogen, the mixture wasfiltered to remove the catalyst, and the filtrate was evaporated. To theresidue was added diisopropyl ether, and the precipitated solid wascollected by filtration and dried to give 2.23 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-(2-ethoxycarbonylethyl)benzamide(Yield: 88.8%) as a white solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.25 (3H, t, J=7.3 Hz), 1.52 (9H, s),2.65 (2H, t, J=7.3 Hz), 3.02 (2H, t, J=7.3 Hz), 4.13 (2H, q, J=7.3 Hz),6.77 (1H, br.s), 7.16-7.33 (5H, m), 7.78 (1H, d, J=8.1 Hz), 7.89 (2H, d,J=8.8 Hz), 9.06 (1H, br.s).

(96-4) To a suspension of 2.21 g of the compound from the process (96-3)(5.36 mmol) in 10 mL of methanol and 15 mL of water was added 0.37 g oflithium hydroxide monohydrate (8.82 mmol), and the mixture was stirredat 40° C. for 3 hours. After cooling, to the mixture was added 10%hydrochloric acid and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and evaporated. Tothe residue was added diisopropyl ether, and the precipitated solid wasfiltered and dried to give 1.87 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-(2-carboxyethyl)benzamide(Yield: 90.8%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (9H, s), 2.59 (2H, t, J=7.3 Hz),2.91 (2H, t, J=7.3 Hz), 7.13-7.20 (2H, m), 7.40 (2H, d, J=8.1 Hz), 7.54(2H, dd, J=7.3, 2.1 Hz), 7.88 (2H, d, J=8.1 Hz), 8.66 (1H, br.s), 9.79(1H, br.s).

(96-5) To a suspension of 0.12 g of the compound from the process (96-4)(0.3 mmol) in 5 mL of benzene were added 0.1 mL of triethylamine (0.7mmol) and 0.3 g of molecular sieves 4A, and the mixture was stirred in astream of nitrogen for 0.5 hours. To the mixture was added 0.15 mL ofdiphenylphosphoryl azide (0.7 mmol), and the mixture was refluxed withheating for 2 hours. After cooling, to the mixture was added 0.4 mL ofbenzyl alcohol (3.8 mmol), and the mixture was refluxed with heating foradditional 2.5 hours. After diluting with ethyl acetate, the reactionmixture was washed with water and saturated brine.

The organic layer was dried and evaporated. The residue was purified bycolumn chromatography on silica gel (eluent: chloroform:ethyl acetate4:1) to give 129 mg ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[2-(N-benzyloxycarbonylamino)ethyl]benzamide(Yield: 88%) as a clear oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 2.89 (2H, t, J=7.3 Hz),3.45-3.54 (2H, m), 4.80 (1H, m), 5.10 (2H, s), 6.76 (1H, br.s),7.20-7.38 (10H, m), 7.79 (1H, d, J=8.8 Hz), 7.89 (2H, d, J=8.1 Hz), 9.10(1H, br.s).

(96-6) To a solution of 129 mg of the compound from the process (96-5)(0.26 mmol) in 10 mL of methanol was added 10% Pd/C (wet, 0.05 g) in astream of nitrogen, and then stirred in a hydrogen stream for 2 hours.After removing the catalyst, the filtrate was evaporated and dried. Theresidue was dissolved in 5 mL of dichloromethane. To the solution wereadded 0.18 g of 3-pyridineacetic acid hydrochloride (1.04 mmol) and then0.28 g of triethylamine (2.0 mmol), and the mixture was ice-cooled.Under ice-cooling, to the mixture was added 0.17 g of2-chloro-1,3-dimethylimidazolinium chloride (1.0 mmol), and the mixturewas stirred for 2 hours. To the mixture was added saturated sodiumbicarbonate aq., and the mixture was extracted with chloroform. Theorganic layer was washed with saturated brine, dried and evaporated. Theresidue was purified by column chromatography on silica gel (eluent:ethyl acetate:methanol=10:1) to give 50 mg ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[2-[N-(pyridin-3-yl)acetylamino]ethyl]benzamide(Yield: 40%) as a colorless oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.48 (9H, s), 2.80 (2H, t, J=6.6 Hz),3.42 (2H, m), 3.52 (2H, s), 6.33 (1H, t-like, J=5.9 Hz), 7.09 (2H, d,J=8.1 Hz), 7.14-7.20 (2H, m), 7.24 (1H, dd, J=4.4, 7.3 Hz), 7.41 (1H,dd, J=3.7, 5.9 Hz), 7.50 (1H, s), 7.58 (1H, dd, J=1.5, 5.9 Hz), 7.69(1H, dd, J=3.7, 5.9 Hz), 7.75 (2H, d, J=8.1 Hz), 8.22 (1H, d, J=2.1 Hz),8.44 (1H, dd, J=1.5, 4.4 Hz), 9.49 (1H, br.s).

(96-7) To a solution of 50 mg of the compound from the process (96-6)(0.10 mmol) in 2 mL of dioxane and 1 mL of methanol was added 2 mL of 4Nhydrochloric acid-dioxane, and the mixture was stirred at roomtemperature for 2.5 hours. To the mixture was added saturated sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and evaporated. Theresidue was dried to give 22 mg ofN-(2-aminophenyl)-4-[2-[N-(pyridin-3-yl)acetylamino]ethyl]benzamide(Yield: 59%) as an amorphous solid.

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.70-2.90 (4H, m),3.42 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H,d, J=7.3 Hz), 6.97 (1H, dd, J=7.3, 7.3 Hz), 7.16 (1H, d, J=7.3 Hz),7.29-7.32 (3H, m), 7.59 (1H, d, J=8.1 Hz), 7.89 (1H, d, J=8.1 Hz), 8.22(1H, t-like), 8.41-8.43 (2H, m), 9.62 (1H, br.s).

Example 97 Preparation ofN-(2-Aminophenyl)-4-[2-[N-(3-picolyl)aminocarbonyl]ethyl]benzamide(Table 1: Compound 80)

(97-1) To a suspension of 0.58 g of the compound from Example 96, theprocess (96-4) (1.5 mmol) in 5 mL of dichloromethane were added 0.22 gof 3-picolylamine (2.0 mmol) and 0.56 mL of triethylamine (4.0 mmol).Under ice-cooling, to the mixture was added 0.39 g of2-chloro-1,3-dimethylimidazolinium chloride (2.0 mmol) in 5 mL ofdichloromethane, and the mixture was stirred for 1.5 hours. To themixture was added saturated sodium bicarbonate aq., and the mixture wasextracted with chloroform.

The organic layer was washed with water and saturated brine, dried andevaporated. The residue was purified by column chromatography on silicagel (eluent: chloroform:methanol:NH₃ aq.=100:10:1) to give 0.71 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[2-[N-(3-picolyl)aminocarbonyl]ethyl]benzamide(Yield: 94%) as a light brown oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.45 (9H, s), 2.42 (2H, t, J=7.3 Hz),2.98 (2H, t, J=7.3 Hz), 4.32 (2H, d, J=6.6 Hz), 6.44 (1H, t, J=6.6 Hz),7.14-7.27 (5H, m), 7.48-7.57 (3H, m), 7.63-7.68 (3H, m), 7.90 (1H, d,J=2.1 Hz), 8.43 (1H, dd, J=1.4, 4.4 Hz), 9.86 (1H, br.s).

(97-2) To a solution of 0.70 g of the compound from the process (97-1)(1.47 mmol) in 5 mL of dioxane was added 5 mL of 4Nhydrochloride-dioxane and then 2 mL of methanol, and the mixture wasstirred at room temperature for 2 hours. To the mixture was addedsaturated sodium bicarbonate aq., and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedand evaporated. To the residue was added diisopropyl ether, and theprecipitated solid was collected by filtration and dried to give 0.42 gof N-(2-aminophenyl)-4-[2-[N-(3-picolyl)aminocarbonyl]ethyl]benzamide(Yield: 76.3%) as an opalescent solid.

mp: 168-170° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.47-2.53 (2H, m),2.93 (2H, t, J=7.3 Hz), 4.27 (2H, d, J=5.9 Hz), 4.90 (2H, br.s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=6.6,7.3 Hz), 7.16 (1H, d, J=6.6 Hz), 7.28-7.35 (1H, m), 7.33 (2H, d, J=8.1Hz), 7.49 (1H, dd, J=2.1, 5.9 Hz), 7.89 (2H, d, J=8.1 Hz), 8.39-8.44(3H, m), 9.62 (1H, br.s); IR (KBr)cm⁻¹: 3313, 1641, 1523, 1457, 1300,748, 713.

Example 98 Preparation ofN-(2-Aminophenyl)-4-[(pyridin-3-yl)methylaminocarbonyloxymethyl]benzamide(Table 1: Compound 85)

(98-1) To a solution of 1.99 g of methyl 4-hydroxymethylbenzoate (12.0mmol) in 20 mL of THF were added 1.78 g of N,N′-carbonyldiimidazole(11.0 mmol) at room temperature, and the solution was stirred for anhour. To the solution were added 1.08 g of 3-picolylamine (10.0 mmol) atroom temperature, and the mixture was stirred for 3.5 hours and leftovernight. Water was added to the solution, and the mixture wasextracted with ethyl acetate.

The organic layer was washed with saturated brine, dried and evaporated.The residue was purified by column chromatography on silica gel (eluent:ethyl acetate) to give 2.76 g ofN-(4-methoxycarbonyl)benzyloxycarbonyl-3-picolylamine (Yield: 91.9%) asa white waxy solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 3.91 (3H, s), 4.40 (2H, d, J=5.9 Hz),5.18 (2H, s), 5.50 (1H, br.s), 7.24-7.28 (1H, m), 7.40 (2H, d, J=8.1Hz), 7.65 (1H, d, J=7.3 Hz), 8.02 (2H, d, J=8.8 Hz), 8.50-8.53 (2H, m).

(98-2) To a suspension of 2.40 g of the compound from the process (98-1)(8.0 mmol) in 10 mL of methanol and 20 mL of water was added 0.42 g oflithium hydroxide monohydrate (10.0 mmol), and the mixture was stirredat room temperature for 5 hours. To the reaction mixture was added 10%hydrochloric acid to acidified to pH 2 to 4, and the precipitated solidwas collected by filtration and dried to give 1.83 g ofN-(4-carboxy)benzyloxycarbonyl-3-picolylamine (79.9%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.24 (2H, d, J=5.9 Hz), 5.13 (2H, s),7.33-7.38 (1H, m), 7.46 (2H, d, J=8.1 Hz), 7.94 (2H, d, J=8.1 Hz),7.95-8.01 (1H, m), 8.46 (1H, d, J=5.1 Hz), 8.49 (1H, d, J=1.5 Hz), 13.0(1H, br.s).

(98-3) To a suspension of 1.26 g of the compound from the process (98-2)(4.4 mmol) in 20 mL of dichloromethane were slowly added 1.0 mL ofoxalyl chloride (11.4 mmol) and then several drops of DMF. The reactionmixture was stirred at room temperature for 10 min. and at 40° C. foradditional 30 min. After cooling, the mixture was evaporated and theexcess oxalyl chloride was removed by evaporation with toluene. To theresidue was added 10 mL of dichloromethane. Under ice-cooling, to themixture was added dropwise a solution of 0.83 g of the compound fromExample 1, the process (1-2) (4.0 mmol) in 8 mL of dichloromethane and 8mL of pyridine, and the solution was warmed to room temperature withstirring for 7 hours and left overnight.

To the mixture was added saturated sodium bicarbonate, and the mixturewas extracted with chloroform. The organic layer was washed withsaturated brine, dried and evaporated. Toluene was added to the residueto azeotropically remove the excess pyridine. The residue was purifiedby column chromatography on silica gel (eluent: ethyl acetate) to give1.40 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[(pyridin-3-yl)methylaminocarbonyloxymethyl]benzamide(Yield: 73.4%) as a light brown solid.

¹H NMR (270MHz, CDCl₃) δ ppm: 1.51 (9H, s), 4.40 (2H, d, J=5.9 Hz), 5.19(2H, s), 5.56 (1H, m), 7.07 (1H, br.s), 7.14-7.31 (4H, s), 7.43 (2H, d,J=8.1 Hz), 7.65 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=7.3 Hz), 7.95 (2H, d,J=8.1 Hz), 8.52 (2H, d, J=4.1 Hz), 9.32 (1H, br.s).

(98-4) To a solution of 1.00 g of the compound from the process (98-3)(2.10 mmol) in 10 mL of dioxane and 2 mL of methanol was added 9 mL of4N hydrochloric acid-dioxane at room temperature, and the mixture wasstirred for 2 hours. To the mixture was added saturated sodiumbicarbonate and the mixture was extracted with ethyl acetate-methylethyl ketone (1:1). The organic layer was washed with saturated brine,dried and evaporated. To the residue was added methanol-diisopropylether, and the precipitated solid was collected by filtration and driedto give 0.79 g ofN-(2-aminophenyl)-4-[(pyridin-3-yl)methylaminocarbonyloxymethyl]benzamide(Yield: quantitative) as a white solid.

mp: 139-141° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.25 (2H, d, J=5.9Hz), 4.90 (2H, s), 5.13 (2H, s), 6.60 (1H, dd, J=6.6, 7.3 Hz), 6.78 (1H,d, J=7.3 Hz), 6.97 (1H, dd, J=6.6, 7.3 Hz), 7.17 (1H, d, J=7.3 Hz), 7.36(1H, dd, J=4.4, 8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.67 (1H, d, J=8.1 Hz),7.97 (2H, d, J=7.3 Hz), 7.90-8.00 (1H, m), 8.46 (1H, dd, J=1.5, 5.1 Hz),8.49 (1H, d, J=2.1 Hz), 9.65 (1H, br.s); IR (KBr)cm⁻¹: 3326 (br.), 1694,1637, 1526, 1458, 1147, 750, 712.

Example 99 Preparation ofN-(2-Aminophenyl)-4-[3-(imidazol-1-yl)propylaminocarbonyloxymethyl]benzamide(Table 1: Compound 215)

The title compound was prepared as described in Example 98.

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.80-1.89 (2H, m),2.94-3.02 (2H, m), 3.98 (2H, t, J=7.3 Hz), 4.88 (2H, s), 5.11 (2H, s),6.55-6.63 (1H, m), 6.76-6.97 (3H, m), 7.10-7.18 (2H, m), 7.43-7.48 (3H,m), 7.61 (1H, s), 7.98 (2H, d, J=8.1 Hz), 9.66 (1H, s).

Example 100 Preparation ofN-(2-Aminophenyl)-4-(phenylacetylamino)benzamide (Table 1: Compound 22)

(100-1) To a solution of 16.6 g of the compound from Example 1, theprocess (1-2) (80 mmol) in 120 mL of dichloromethane was added 16.8 mLof triethylamine (120 mmol) and then, was slowly added a solution of16.0 g of 4-nitrobenzoyl chloride (86.4 mmol) in 40 mL ofdichloromethane, and the solution was stirred for 7 hours. To thesolution, was added saturated sodium bicarbonate aq., and the mixturewas extracted with chloroform.

The organic layer was washed with 1N hydrochloric acid, saturated sodiumbicarbonate and saturated brine; dried; and evaporated. The residue waswashed with diisopropyl ether to give 28.0 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-nitrobenzamide (Yield: 98%)as a light yellow solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.53 (9H, s), 7.17-7.29 (4H, m), 7.85(1H, br.d, J=7.3 Hz), 8.17 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz),9.88 (1H, br.s).

(100-2) To a solution of 24.0 g of the compound from the process.(100-1) (67.2 mmol) in 80 mL of THF and 80 mL of methanol was added 2.4g of 10% Pd/C (wet) in a stream of nitrogen, and the mixture was stirredin a stream of hydrogen for 1.5 hours. After cease of absorption ofhydrogen, the catalyst was removed by filtration and the filtrate wasevaporated. To the residue were added diisopropyl ether and ethylacetate, and the precipitated solid was collected by filtration anddried to give 18.96 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-aminobenzamide (Yield: 86%)as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.46 (9H, s), 5.84 (2H, s), 6.61 (2H,d, J=8.8 Hz), 7.10-7.18 (2H, m), 7.46-7.55 (2H, m), 7.68 (2H, d, J=8.8Hz), 8.67 (1H, s), 9.49 (1H, s).

(100-3) To a solution of 1.6 g of the compound from the process (100-2)(4.88 mmol) in 15 mL of dichloromethane were added 0.8 mL of pyridine(9.9 mmol) and 0.96 mL of phenylacetyl chloride (7.26 mmol), and thesolution was stirred for one day. After completion of the reaction,water was added and the precipitated crystals were collected byfiltration to give 1.66 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-(phenylacetylamino)benzamide(Yield: 76%).

(100-4) To a solution of 1 g of the compound from the process (100-3)(2.24 mmol) in 25 mL of acetonitrile was added 0.88 mL ofiodotrimethylsilane (6.18 mmol) at room temperature, and the solutionwas stirred for 3 hours. After completion of the reaction, the solutionwas concentrated. The residue was recrystallized from methanol to give0.29 g of N-(2-aminophenyl)-4-(phenylacetylamino)benzamide (Yield: 38%)as white crystals.

mp: 232-237° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.69 (2H, s), 4.90(2H, s), 6.60 (1H, t, J=7.3 Hz), 6.77 (1H, d, J=7.3 Hz), 6.96 (1H, t,J=7.3 Hz), 7.15 (1H, d, J=7.4 Hz), 7.22-7.35 (5H, m), 7.72 (2H, d, J=8.8Hz), 7.95 (2H, d, J=8.8 Hz), 9.57 (1H, s), 10.43 (1H, s); IR (KBr)cm⁻¹:2937, 2764, 1660, 1598, 1506, 1459.

As described in Example 100, the compounds of Examples 101 to 128 wereprepared, each of whose melting point (mp), ¹H NMR data and/or IR dataare shown below.

Example 101 N-(2-Aminophenyl)-4-[(4-phenylbutanoyl)amino]benzamide(Table 1: Compound 4)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.91 (2H, hep, J=7.3Hz), 2.37 (2H, t, J=7.3 Hz), 2.64 (2H, t, J=7.3 Hz), 5.0 (2H, br.s),6.61 (1H, t, 7.0 Hz), 6.79 (1H, dd, J=1.5, 8.1 Hz), 6.97 (1H, t, J=77.0Hz), 7.10-7.40 (6H, m), 7.71 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz),9.57 (1H, s), 10.15 (1H, s); IR (KBr)cm⁻¹: 3344, 1687, 1603, 1542, 1460,1315, 1033, 842, 737.

Example 102 N-(2-Aminophenyl)-4-[(4-chlorophenylacetyl)amino]benzamide(Table 1: Compound 15)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.72 (2H, s),7.29-7.43 (8H, m), 7.77 (2H, d, J=8.8 Hz), 8.00 (2H, d, J=8.8 Hz), 10.29(1H, s), 10.52 (1H, s); IR (KBr)cm⁻¹: 3300, 2868, 1664, 1638, 1520.

Example 103 N-(2-Aminophenyl)-4-[(2-nitrophenylacetyl)amino]benzamideHydrochloride (Table 1: Hydrochloride of Compound 19)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.20 (2H, s),7.20-7.30 (3H, m), 7.40-7.45 (1H, m), 7.60 (2H, d), 7.71-7.77 (3H, m),8.02-8.10 (4H, m), 10.27 (1H, br.s), 10.64 (1H, br.s); IR (KBr)cm⁻¹:3263; 1676, 1647, 1518, 1184, 759.

Example 104 N-(2-Aminophenyl)-4-[(4-nitrophenylacetyl)amino]benzamide(Table 1: Compound 21)

mp: 222-226° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.90 (2H, s), 4.96(2H, br.s), 6.60 (1H, dt, J=1.5, 6.6 Hz), 6.78 (1H, dd, J=1.5, 6.6 Hz),6.97 (1H, dt, J=1.5, 6.6 Hz), 7.15 (1H, dd, J=1.5, 6.6 Hz), 7.63 (2H, d,J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 8.22 (2H, d,J=8.8 Hz), 9.59 (1H, s), 10.54 (1H, s); IR (KBr)cm⁻¹: 3395, 3334, 1671,1630, 1519, 1346.

Example 105 N-(2-Aminophenyl)-4-[(2-aminophenylacetyl)amino]benzamide(Table 1: Compound 22)

mp: 177-182° C.(dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.54 (2H, s),4.88 (2H, br.s), 5.09 (2H, br.s), 6.55 (1H, dd, J=6.6, 7.3 Hz), 6.59(1H, dd, J=7.3, 7.3 Hz), 6.68 (1H, d, J=7.3 Hz), 6.78 (1H, d, J=7.3 Hz),6.96 (2H, dd, J=7.3, 7.3 Hz), 7.06 (1H, d, J=6.6 Hz), 7.15 (1H, d, J=7.3Hz), 7.71 (2H, d, J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 9.57 (1H, br.s),10.39 (1H, br.s); IR (KBr)cm⁻¹: 3374, 3256 (br.), 1683, 1597, 1503,1317, 1262, 1180, 1153, 747.

Example 106 N-(2-Aminophenyl)-4-[(4-aminophenylacetyl)amino]benzamide(Table 1: Compound 26)

mp: 219-226° C.(dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.46 (2H, s),4.93 (4H, br.s), 6.52 (2H, d, J=8.1 Hz), 6.59 (1H, dt, J=1.5, 7.3 Hz),6.77 (1H, dd, J=1.4, 7.3 Hz), 6.97 (1H, dt, J=1.4, 7.3 Hz), 6.99 (2H, d,J=8.1 Hz), 7.15 (1H, dd, J=1.5, 7.3 Hz), 7.70 (2H, d, J=8.8 Hz), 7.93(2H, d, J=8.8 Hz); IR (KBr)cm⁻¹: 3278, 3032, 1675, 1628, 1516.

Example 107 N-(2-Aminophenyl)-4-[(4-methoxyphenylacetyl)amino]benzamide(Table 1: Compound 32)

mp: (amouphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.62 (2H, s), 3.74(3H, s), 6.90 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.8 Hz), 7.30 (3H, m),7.39 (1H, m), 7.77 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=8.8 Hz), 10.26 (1H,s), 10.44 (1H, s); IR (KBr)cm⁻¹: 3300, 2759, 1670, 1638, 1514, 1250.

Example 108N-(2-Aminophenyl)-4-[[4-(N,N-dimethylamino)phenylacetyl]amino]benzamide(Table 1: Compound 53)

mp: 140° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.04 (6H, s), 3.67 (2H,s), 7.16 (2H, d, J=8.0 Hz), 7.29-7.40 (6H, m), 7.76 (2H, d, J=8.8 Hz),7.99 (2H, d, J=8.8 Hz), 10.29 (1H, s), 10.47 (1H, s); IR (KBr)cm⁻¹:3244, 2951, 2639, 1647, 1599, 1507.

Example 109N-(2-Aminophenyl)-4-[(4-trifluoromethylphenylacetyl)amino]benzamide(Table 1: Compound 43)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.84 (2H, s), 6.89(1H, t, J=7.4 Hz), 7.00 (1H, d, J=7.4 Hz), 7.11 (1H, t, J=7.4 Hz), 7.25(1H, d, J=7.4 Hz), 7.57 (2H, d, J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 7.73(2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 9.87 (1H, s), 10.54 (1H, s);IR (KBr)cm⁻¹: 3260, 1664, 1605, 1521, 1327, 1119.

Example 110 N-(2-Aminophenyl)-4-[(pyridin-2-yl)acetylamino]benzamideDihydrochloride (Table 1: Hydrochloride of Compound 174)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.60 (2H, s),7.30-7.46 (3H, m), 7.56 (1H, d, J=7.4 Hz), 7.79 (2H, d, J=8.8 Hz), 7.95(1H, t, J=6.6 Hz), 8.01 (1H, d, J=7.4 Hz), 8.11 (2H, d, J=8.8 Hz), 8.49(1H, t, J=7.4 Hz), 8.87 (1H, d, J=5.1 Hz), 10.46 (1H, s).

Example 111 N-(2-Aminophenyl)-4-[(pyridin-3-yl)acetylamino]benzamideDihydrochloride (Table 1: Hydrochloride of Compound 68)

mp: 182-189° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.12 (2H, s),7.29-7.59 (4H, m), 7.80 (2H, d, J=8.8 Hz), 8.05 (1H, m), 8.11 (2H, d,J=8.8 Hz), 8.57 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.2 Hz), 8.95 (1H, s),10.25 (1H, s), 10.48 (1H, s).

Example 112N-(2-Aminophenyl)-4-[[3-(pyridin-3-yl)propanoyl]amino]benzamide (Table1: Compound 69)

mp: 184-186° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.80 (2H, t, J=7.3Hz), 3.08 (2H, t, J=7.3 Hz), 6.87 (1H, t, J=8.0 Hz), 6.99 (1H, dd,J=1.4, 8.0 Hz), 7.11 (1H, dt, J=1.4, 8.0 Hz), 7.25 (1H, d, J=8.0 Hz),7.70 (2H, d, J=8.8 Hz), 7.77 (1H, dd, J=5.8, 8.0 Hz), 7.96 (2H, d, J=8.8Hz), 8.22 (1H, d, J=8.0 Hz), 8.75 (1H, d, J=1.4 Hz), 9.83 (1H, s), 10.25(1H, s).

Example 113N-(2-Aminophenyl)-2-chloro-4-[3-(pyridin-3-yl)propanoylamino]benzamide(Table 1: Compound 123)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.70 (2H, t, J=8.1Hz), 2.96 (2H, t, J=7.3 Hz), 4.74 (2H, br.s), 6.60 (1H, t, J=6.6 Hz),6.78 (1H, d, J=6.6 Hz), 6.95 (1H, t, J=6.6 Hz), 7.19 (1H, dd, J=1.5, 7.3Hz), 7.29 (1H, dd, J=5.1, 7.3 Hz), 7.66 (2H, d, J=8.8 Hz), 7.92 (2H, d,J=8.8 Hz), 8.48 (1H, d, J=2.2 Hz), 9.37 (1H, s), 10.00 (1H, s); IR(KBr)cm⁻¹: 3273, 1675, 1519, 1315, 1181, 852, 747.

Example 114N-(2-Aminophenyl)-4-[[N-(pyridin-3-yl)methyl-N-trifluoroacetylamino]acetylamino]benzamide(Table 1: Compound 107)

mp: 145° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.18 and 4.42(total 2H, s), 4.73 and 4.83 (total 2H, s), 4.87 (2H, br.s), 6.60 (1H,dd, J=7.3, 8.1 Hz), 6.78 (1H, d, J=8.1 Hz), 6.96 (H, dd, J=7.3, 7.3 Hz),7.16 (1H, d, J=8.1 Hz), 7.35-7.45 (1H, m), 7.66 (2H, d, J=5.9 Hz),7.70-7.80 (1H, m), 7.90-8.00 (2H, m), 8.51-8.55 (1H, m), 8.58 (1H, s),9.60 (1H, br.s), 10.36 and 10.43 (total 1H, br.s).

Example 115N-2-Aminophenyl)-4-[[N-(pyridin-3-yl)methylamino]acetylamino]benzamide(Table 1: Compound 105)

mp: 160° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.30 (2H, s), 3.79(2H, s), 4.88 (2H, s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=8.1 Hz), 7.74 (2H, d,J=8.8 Hz), 7.80 (1H, d, J=7.3 Hz), 7.95 (2H, d, J=8.1 Hz), 8.46 (1H, d,J=3.7 Hz), 8.57 (1H, s), 9.57 (1H, s), 10.08 (1H, br.s); IR (KBr)cm⁻¹:3298, 1693, 1637, 1602, 1544, 1454, 1262, 848, 762.

Example 116N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)-methyloxamoylamino]benzamide(Table 1: Compound 104)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.43 (2H, d, J=6.6Hz), 4.90 (2H, br.s), 6.60 (1H, dd, J=6.6, 7.3 Hz), 6.78 (1H, d, J=7.3Hz), 6.97 (1H, ddd, J=1.5, 6.6, 7.3 Hz), 7.16 (1H, d, J=7.3 Hz), 7.37(1H, dd, J=4.4, 8.1 Hz), 7.73 (1H, d, J=8.1 Hz), 7.96 and 7.96 (4H,AA′BB′, J=9.4 Hz), 8.47 (1H, dd, J=1.5, 5.1 Hz), 8.56 (1H, d, J=1.5 Hz),9.59 (1H, s), 9.67 (1H, t, J=6.6 Hz), 10.92 (1H, br.s); IR (KBr)cm⁻¹:3299, 1644, 1518, 1320, 1119, 748.

Example 117N-(2-Aminophenyl)-4-[[N-(pyridin-3-yl)methyl-N-nicotinoylamino]acetylamino]benzamide(Table 1: Compound 106)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.11 (major 2H, s),4.26 (minor 2H, s), 4.75 (major 2H, s), 4.65 (minor 2H, s), 4.88 (total2H, br.s), 6.60 (total 1H, dd, J=7.3, 8.1 Hz), 6.78 (total 1H, d, J=7.3Hz), 6.97 (total 1H, dd, J=7.3, 8.1 Hz), 7.15 (total 1H, d, J=8.1 Hz),7.41-7.95 (total 8H, m), 8.46-8.52 (total 1H, m), 8.63-8.70 (total 2H,m), 9.59 (total 1H, s), 10.22 (major 1H, br.s), 10.37 (minor 1H, br.s);IR (KBr)cm⁻¹: 3269, 1701, 1637, 1603, 1534, 1506, 1312, 1254, 752.

Example 118N-(2-Aminophenyl)-4-[[4-(pyridin-3-yl)butanoyl]amino]benzamide (Table 1:Compound 70)

mp: 165-167° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.88-1.99 (2H,m), 2.68 (2H, t, J=7.3 Hz), 2.39 (2H, t, J=7.3 Hz), 6.78-6.81 (1H, m),6.94-6.99 (1H, m), 7.15-7.18 (1H, m), 7.34-7.39 (1H, m), 7.69-7.72 (1H,m), 7.94 (2H, d, J=8.8 Hz), 8.43-8.48 (2H, m); IR (KBr)cm⁻¹: 3291, 1660,1626, 1308, 1261, 1182, 1027, 825, 747.

Example 119N-(2-Aminophenyl)-4-[[N-(pyridin-3-yl)methyl-N-methylamino]acetylamino]benzamide(Table 1: Compound 108)

mp: 154-155° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.28 (3H, s), 3.27(2H, s), 3.71 (2H, s) 4.88 (2H, br.s), 6.60 (1H, dd, J=6.6, 7.3 Hz),6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d, J=8.1Hz), 7.38 (1H, dd, J=2.9, 8.1 Hz), 7.77 (2H, d, J=8.8 Hz), 7.75-7.85(1H, m), 7.95 (2H, d, J=8.8 Hz), 8.47 (1H, d, J=1.5 Hz), 8.49 (1H, s),9.56 (1H, s), 10.62 (1H, br.s).

Example 120N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)oxyacetylamino]benzamide (Table 1:Compound 65)

mp: 175-179° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.86 (2H, s), 4.90(2H, br.s), 6.60 (1H, d, J=7.3, 7.3. Hz), 6.78 (1H, d, J=7.3 Hz), 6.97(1H, dd, J=6.6, 7.3 Hz), 7.16 (1H, d, J=8.1 Hz), 7.34-7.47 (2H, m), 7.76(2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz), 8.22 (1H, d, J=3.6 Hz), 8.39(1H, d, J=2.9 Hz), 9.60 (1H, br.s), 10.40 (1H, br.s); IR (KBr)cm⁻¹:3321, 1655, 1530, 1276, 1231, 1068, 757.

Example 121N-(2-Aminophenyl)-4-[4-(pyridin-3-yl)-1,4-dioxobutylamino]benzamide(Table 1: Compound 99)

mp: 190-194° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.08 (2H, t, J=6.4Hz), 3.41 (2H, t, J=6.4 Hz), 4.86 (2H, s), 6.59 (1H, t, J=5.6 Hz), 6.78(1H, d, J=7.9 Hz), 6.96 (1H, t, J=7.4 Hz), 7.15 (1H, d, J=7 Hz), 7.58(1H, dd, J=4.9, 7.9 Hz), 7.70 (2H, d, J=8.9 Hz), 7.94 (2H, d, J=8.9 Hz),8.35 (1H, d, J=7.9 Hz), 8.81 (1H, d, J=4 Hz), 9.18 (1H, s), 9.56 (1H,s), 10.32 (1H, s); IR (KBr)cm⁻¹: 3317, 1691, 1652, 1601, 1522, 1312,982, 847, 764, 701.

Example 122N-(2-Aminophenyl)-4-[3-[N-(pyridin-3-yl)amino]-1,3-dioxopropylamino]benzamide(Table 1: Compound 94)

mp: 196° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.57 (2H, s), 4.87(2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m),7.14-7.17 (1H, m), 7.33-7.38 (11H, m), 7.73 (2H, d, J=8.8 Hz), 7.97 (2H,d, J=8.8 Hz), 8.05-8.08 (1H, m), 8.27-8.30 (1H, m), 8.75-8.76 (1H, m),9.59 (1H, s), 10.44 (1H, s), 10.47 (1H, s); IR (KBr)cm⁻¹: 3410, 3315,1685, 1655, 1625, 1536, 1428, 1362, 1263, 1201, 744.

Example 123N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxyacetylamino]-3-methylbenzamide(Table 1: Compound 102)

mp: 178-181° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.28 (3H, s),4.22 (2H, s), 4.71 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.16 (1H, d,J=7.3 Hz), 7.43 (1H, dd, J=4.4, 8.1 Hz), 7.71 (1H, d, J=8.1 Hz),7.79-7.89 (3H, m), 8.54 (1H, dd, J=1.5, 4.4 Hz), 8.66 (1H, d, J=1.5 Hz),9.36 (1H, br.s), 9.60 (1H, br.s); IR (KBr)cm⁻¹: 3394, 3269, 1683, 1630,1593, 1521, 1460, 1131, 750, 716.

Example 124N-(2-Aminophenyl)-4-[N-(thiophen-3-yl)methoxyacetylamino]benzamide(Table 1: Compound 204)

mp: 186-189° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.11 (2H, s), 4.63(2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d,J=8.1 Hz), 6.97 (1H, dd, J=7.3, 7.3 Hz), 7.12-7.19 (2H, m), 7.53-7.57(2H, m), 7.78 (2H, d, J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 9.58 (1H,br.s), 10.04 (1H, br.s); IR (KBr)cm⁻¹: 3341, 3248, 1694, 1631, 1611,1506, 1314, 1126.

Example 125N-(2-Aminophenyl)-4-[N-methyl-N-(pyridin-3-yl)methoxyacetylamino]benzamide(Table 1: Compound 103)

mp: 180-183° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.24 (3H, s),4.08 (2H, br.s), 4.50 (2H, s), 4.94 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3Hz), 6.79 (1H, d, J=8.1 Hz), 6.98 (1H, dd, J=1.3, 8.1 Hz), 8.03 (1H, d,J=8.1 Hz), 8.48-8.50 (2H, m), 9.72 (1H, br.s); IR (KBr)cm⁻¹: 3395, 3283,1683, 1639, 1604, 1506, 1459, 1307, 1124.

Example 126N-(2-Aminophenyl)-4-[N-(pyridin-2-yl)methoxyacetylamino]benzamide (Table1: Compound 176)

mp: 171-173° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.26 (2H, s), 4.74(2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J=6.6, 8.1 Hz), 6.78 (1H, d,J=7.3 Hz), 6.97 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16 (1H, d, J=7.3 Hz),7.35 (1H, dd, J=5.1, 6.6 Hz), 7.80 (2H, d, J=8.1 Hz), 7.80-7.89 (1H, m),7.97 (2H, d, J=8.1 Hz), 8.59 (1H, d, J=4.4 Hz), 9.59 (1H, br.s), 10.30(1H, br.s); IR (KBr)cm⁻¹: 3391, 3258, 1678, 1629, 1593, 1517, 1128, 767,742.

Example 127N-(2-Aminophenyl)-4-[N-(N-nicotinoylamino)acetylamino]benzamide (Table1: Compound 97)

mp: 218-220° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.13 (2H, d,J=5.9 Hz), 4.89 (2H, s), 6.59 (1H, dd, J=7.3, 7.3 Hz), 6.77 (1H, d,J=8.1 Hz), 6.96 (1H, dd, J=7.3, 8.1 Hz), 7.15 (1H, d, J=7.3 Hz), 7.55(1H, dd, J=5.1, 8.1 Hz), 7.73 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz),8.25 (1H, d, J=8.1 Hz), 8.74 (1H, d, J=5.1 Hz), 9.07 (1H, d, J=1.5 Hz),9.13 (1H, t-like, J=5.9 Hz), 9.58 (1H, s), 10.36 (1H, s).

Example 128N-(2-Aminophenyl)-5-[3-(pyridin-3-yl)propionamide]benzofuran-2-carboxyamide(Table 3: Compound 1)

mp: 267-272° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.51 (2H, t, J=7.3Hz), 2.97 (2H, t, J=7.3 Hz), 6.61 (1H, dd, J=8.1, 8.8 Hz), 6.80 (1H, dd,J=1.5, 8.1 Hz), 6.99 (1H, dd, J=8.1, 8.8 Hz), 7.20 (1H, dd, J=1.5, 8.1Hz), 7.32 (1H, dd, J=5.2, 8.1 Hz), 7.49 (1H, dd, J=1.5, 8.8 Hz), 7.61(1H, d, J=8.8 Hz), 7.67 (1H, s), 7.70 (1H, m), 8.15 (1H, d, J=1.5 Hz),8.40 (1H, dd, J=1.5, 5.2 Hz), 8.51 (1H, d, J=1.5 Hz), 9.84 (1H, s), 10.1(1H, s); IR (KBr)cm⁻¹: 3333, 3272, 1666, 1583, 1561, 1458, 1314, 1247,1143, 807, 746, 713.

Example 129 Preparation ofN-(2-Aminophenyl)-4-[N-[2-(pyridin-3-yl)oxypropionyl]amino]benzamide(Table 4: Compound 2)

(29-1) In 10 mL of dichloromethane were dissolved 0.34 g of the compoundfrom Example 47, the process (47-2) (1.2 mmol) and 0.34 g of thecompound from Example 100, the process (100-2) (1.0 mmol), and then 0.5mL of triethylamine (3.6 mmol). Under ice-cooling, to the solution wasadded 0.21 g of 2-chloro-1,3-dimethylimidazolidinium chloride (1.24mmol) in 5 mL of dichloromethane, and the solution was stirred underice-cooling for 2 hours. After neutralizing with saturated sodiumbicarbonate aq., the mixture was diluted with water and extracted withchloroform. The organic layer was washed with saturated brine, dried andevaporated. The residue was purified by column chromatography on silicagel (eluent: ethyl acetate:methanol=10:1) to give 0.68 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-[N-[2-(pyridin-3-yl)oxypropionyl]amino]benzamideas a mixture with 1,3-dimethyl-2-imidazolinone.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.52 (9H, s), 1.70 (3H, d, J=6.6 Hz),4.84 (1H, q, J=6.6 Hz), 6.89 (1H, br.s), 7.12-7.31 (6H, m), 7.68 (2H, d,J=8.8 Hz), 7.79 (1H, d, J=8.1 Hz), 7.96 (2H, d, J=8.8 Hz), 8.34 (1H, d,J=2.9, 2.9 Hz), 8.43 (1H, d, J=1.5 Hz), 9.25 (1H, br.s).

(129-2) To a solution of 0.68 g of the compound from the process (129-1)in 5 mL of dichloromethane was added 10 mL of 15% (vol/vol)trifluoroacetic. acid/dichloromethane, and the solution was stirred atroom temperature for 4.5 hours. After neutralizing the solution withsaturated sodium bicarbonate aq., dichloromethane was removed byevaporation. The solution was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried and evaporated. To theresidue were added methanol and diisopropyl ether, and the precipitatedsolid was collected by filtration and dried to give 0.22 g ofN-(2-aminophenyl)-4-[N-[2-(pyridin-3-yl)oxypropionyl]amino]benzamide(Yield: 5.8% for the 2 steps) as an opalescent solid.

mp: 193-196° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.60 (3H, d, J=6.6Hz), 4.88 (2H, br.s), 5.04 (1H, q, J=6.6 Hz), 6.60 (1H, dd, J=6.6, 7.3Hz), 6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=7.3, 8.1 Hz), 7.15 (1H, d,J=7.3 Hz), 7.32-7.39 (2H, m), 7.75 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.1Hz), 8.20 (1H, dd, J=1.5, 3.7 Hz), 8.35 (1H, d, J=2.1 Hz), 9.59 (1H,br.s), 10.44 (1H, br.s).

Example 130 Preparation ofN-(2-Aminophenyl)-4-[(pyridin-3-yl)methoxyacetylamino]benzamide (Table1: Compound 101)

(130-1) To a suspension of 4.4 g of sodium hydride (60% oil dispersion;110 mmol) in 300 mL of THF were added dropwise 10.91 g of3-pyridinemethanol (100 mmol) in 20 mL of THF at room temperature, andthe mixture was stirred at room temperature for 2 hours. The resultingwhite suspension was ice-cooled, and 19.51 g of tert-butyl bromoacetate(100 mmol) in 20 mL of THF was added dropwise, maintaining the innertemperature within 10 to 12° C. The suspension was warmed to roomtemperature with stirring for 3 hours, and then left overnight. Afteradding water and saturated sodium bicarbonate aq., the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried and evaporated. The residue was purified bycolumn chromatography on silica gel (gradient elution withn-hexane:ethyl acetate=1:1 to ethyl acetate) to give 7.56 g oftert-butyl (pyridin-3-yl)methoxyacetate (33.8%) as a light brown oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.49 (9H, s), 4.03 (2H, s), 4.64 (2H, s),7.30 (1H, dd, J=4.9, 7.3 Hz), 7.76 (1H, d, J=7.3 Hz), 8.56 (1H, d, J=4.9Hz), 8.60 (1H, s).

(130-2) Under ice-cooling, 12 mL of trifluoroacetic acid was added to3.5 g of the compound from the process (130-1) (15.7 mmol), and thesolution was stirred at room temperature for 6 hours. Part oftrifluoroacetic acid was removed by evaporation to give a mixture of(pyridin-3-yl)methoxyacetic acid and trifluoroacetic acid (6.5 g). Themixture was dissolved in 70 mL of dichloromethane. To the solution wasadded 25 mL of pyridine and then, was slowly added dropwise underice-cooling, 2.37 g of 2-chloro-1,3-dimethylimidazolinium chloride (14.0mmol) in 20 mL of dichloromethane over 30 min, and the solution wasstirred under ice-cooling for additional 5 hours. To the solution wasadded saturated sodium bicarbonate aq., and stirring was continued untilfoaming ceased. The mixture was extracted with chloroform. The organiclayer was washed with saturated brine, dried and evaporated. The residuewas purified by column chromatography on silica gel (gradient elutionwith ethyl acetate to ethyl acetate:methanol=10:1) to give 4.78 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)methoxyacetylamino]benzamide(Yield: 62%) as a 1:1 (molar ratio) mixture with DMI(1,3-dimethyl-2-imidazolinone).

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 4.15 (2H, s), 4.70 (2H, s),6.92 (1H, br.s), 7.15-7.29 (3H, m), 7.37 (1H, dd, J=7.3, 5.1 Hz), 7.67(2H, d, J=8.8 Hz), 7.71-7.79 (2H, m), 7.96 (2H, d, J=8.8 Hz), 8.41 (1H,s), 8.62-8.66 (2H, m), 9.23 (1H, br.s).

(130-3) To a solution of 2.39 g of the compound from the process (130-2)(4.0 mmol) in 28 mL of dichloromethane was added 55 mL of 15% (vol/vol)trifluoroacetic acid/dichloromethane, and the solution was stirred atroom temperature for 7 hours. The solution was neutralized withsaturated sodium bicarbonate, and then water was added. The reactionmixture was stirred at room temperature and extracted with a 2:1 mixtureof ethyl acetate-methyl ethyl ketone, a 2:1 mixture of ethylacetate-THF, and ethyl acetate, in sequence. The combined organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.After removing the dehydrating reagent by filtering, the filtrate wasconcentrated. To the residue thus obtained were added methanol anddiisopropyl ether, and the precipitated solid was collected byfiltration and dried to give 1.29 g ofN-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxyacetylamino]benzamide(Yield: 85.6%) as a dark brown solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.19 (2H, s), 4.68 (2H, s), 4.90 (2H,br.s), 6.60 (1H, ddd, J=1.5, 7.3, 8.1 Hz), 6.78 (1H, dd, J=1.5, 8.1 Hz),6.97 (1H, dd, J=7.3, 7.3 Hz), 7.15 (1H, d, J=7.3 Hz), 7.42 (1H, dd,J=4.4, 8.1 Hz), 7.77 (2H, d, J=8.8 Hz), 7.85 (1H, d, J=7.3 Hz), 7.96(2H, d, J=8.8 Hz), 8.54 (1H, dd, J=1.5, 5.1 Hz), 8.63 (1H, s), 9.58 (1H,s), 10.09 (1H, s); IR (KBr)cm⁻¹: 3403, 3341, 3250, 1694, 1630, 1610,1506, 1314, 1259, 1118, 764.

Example 131 Preparation ofN-(2-Aminophenyl)-4-[N-[2-(pyridin-3-yl)methoxypropionyl]amino]benzamide(Table 4: Compound 1)

(131-1) To a suspension of 1.24 g of sodium hydride (60% oil dispersion;31 mmol) in 90 mL of THF were added dropwise 3.27 g of3-pyridinemethanol (30 mmol) in 10 mL of dry THF at room temperatureover 5 min. The resulting white suspension was stirred at roomtemperature for an hour, to which was then added dropwise 6.27 g oftert-butyl 2-bromopropionate (30 mmol) in 10 mL of dry THF at roomtemperature over 5 min. The mixture was stirred at room temperature for11.5 hours. After adding water, the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried andevaporated. The residue was purified by column chromatography on silicagel (eluent: n-hexane:ethyl acetate=1:1) to give 4.01 g of tert-butyl(pyridin-3-yl)methoxyacetate (Yield: 56.3%) as a dark brown oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.42 (3H, d, J=7.3 Hz), 1.50 (9H, s),3.96 (1H, q, J=6.6 Hz), 4.47, 4.69 (2H, ABq, J=11.0 Hz), 7.29 (1H, dd,J=5.1, 8.1 Hz), 7.75 (1H, d, J=8.1 Hz), 8.5 (1H, d, J=4.4 Hz), 8.60 (1H,s).

(131-2) To a solution of 1.09 g of the compound from the process (131-1)(4.59 mmol) in 5 mL of dichloromethane was added 8 mL of trifluoroaceticacid, and the solution was stirred at room temperature for 9.5 hours.After evaporation, to the residue was added 25 mL of dichloromethane and3 mL of pyridine. Under ice-cooling, to the solution was added dropwise0.70 g of 2-chloro-1,3-dimethylimidaolidinium chloride (4.1 mmol) in8.mL of dichloromethane, and then the mixture was stirred for 30 min. Tothe solution was slowly added dropwise 0.98 g of the compound fromExample 100, the process (100-2) (3.0 mmol) in 20 mL of dichloromethaneand 10 mL of pyridine under ice-cooling over 15 min, and the solutionwas warmed to room temperature with stirring for 8 hours. After addingsaturated sodium bicarbonate aq., the mixture was diluted with water andextracted with chloroform. The organic layer was washed with saturatedbrine, dried and evaporated. The residue was purified by columnchromatography on silica gel (eluent: ethyl acetate:methanol=8:1) togive 1.19 g ofN-[2-(N-tert-butoxycabonylamino)phenyl]-4-[N-[2-(pyridin-3-yl)methoxypropionyl]amino]benzamideas a 2:3 (molar ratio) mixture with 1,3-dimethyl-2-imidazolinone.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 1.54 (3H, d, J=6.6 Hz),4.13 (1H, q, J=6.6 Hz), 4.65, 4.71 (2H, ABq, J=11.7 Hz), 7.12-7.18 (2H,m), 7.28-7.37 (3H, m), 7.65 (2H, d, J=8.1 Hz), 7.73 (2H, br.d, J=5.9Hz), 7.96 (2H, d, J=8.8 Hz), 8.59-8.64 (3H, m), 9.39 (1H, br.s).

(131-3) To a solution of 1.19 g of the compound from the process (131-2)(1.8 mmol) in 10 mL of, dichloromethane was added 20 mL of 15% (vol/vol)trifluoroacetic acid in dichloromethane, and the solution was stirred atroom temperature for 4.5 hours. The solution was poured into saturatedsodium bicarbonate, and dichloromethane was removed by evaporation. Theresulting aqueous layer was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried and evaporated. To theresidue were added methanol and diisopropyl ether, and the precipitatedsolid was collected by filtration and dried to give 585 mg ofN-(2-aminophenyl)-4-[N-[2-(pyridin-3-yl)methoxypropionyl]amino]benzamideas a light brown solid.

mp: 144-148° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.40 (3H, d, J=6.6Hz), 4.14 (1H, q, J=6.6 Hz), 4.56 and 4.65 (2H, ABq, J=11.8 Hz), 4.89(2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz), 6.97(1H, dd, J=6.6, 7.3 Hz), 7.16 (1H, d, J=7.3 Hz), 7.40 (1H, dd, J=4.4 Hz,7.3 Hz), 7.78-7.85 (3H, m), 7.97 (2H, d, J=8.8 Hz), 8.52 (1H, dd, J=1.5,5.1 Hz), 8.61 (1H, d, J=2.1 Hz), 9.60 (1H, s), 10.15 (1H, s).

Example 132 Preparation ofN-(2-Aminophenyl)-4-(N-benzylamino)carbonylbenzamide (Table 1: Compound8)

(132-1) To a suspension of 13.0 g of monomethyl terephthalate (72.2mmol) in 100 mL of toluene was added dropwise 10 mL of thionyl chlorideat room temperature. After stirring at 80° C. for 3 hours, the solventand an excess amount of thionyl chloride were removed by evaporation.The residue was suspended in 100 mL of dioxane, and 9.98 g of2-nitroaniline (72.2 mmol) were added to the suspension, followed byrefluxing with heating for 4 hours.

After cooling and evaporation, the residue was washed with methanol togive 20.3 g of N-(2-nitrophenyl)-4-methoxycarbonylbenzamide (Yield:93.7%) as a yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.91 (3H, s), 7.43-7.49 (1H, m),7.76-7.78 (2H, m), 8.03 (1H, d, J=8.1 Hz), 8.08 (2H, d, J=8.8 Hz), 8.14(2H, d, J=8.8 Hz), 10.94 (1H, s).

(132-2) To a solution of 4.24 g of the compound from the process (132-1)in 50 mL of THF and 50 mL of methanol was added 0.4 g of 10% Pd/C in astream of nitrogen, and the mixture was stirred in a stream of hydrogenfor 1.5 hours. The catalyst was removed by filtration, and the filtratewas evaporated. The residue was washed with methanol to give 3.4 g ofN-(2-aminophenyl)-4-methoxycarbonylbenzamide (Yield: 87.5%) as a lightyellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.90 (3H, s), 4.95 (2H, s), 6.60 (1H,dd, J=7.3, 8.1 Hz), 6.78 (1H, d, J=7.3 Hz), 6.99 (1H, dd, J=7.3, 7.3Hz), 7.17 (1H, d, J=7.3 Hz), 8.08 (2H, d, J=8.1 Hz), 8.11 (2H, d, J=8.1Hz), 9.85 (1H, s).

(132-3) To a solution of 2.71 g of the compound from the process (132-2)(10.0 mmol) in 100 mL of dioxane and 50 mL of water was added 5% sodiumhydroxide aq. under ice-cooling, and then were added dropwise 2.62 g ofdi-tert-butyl dicarbonate (12.0 mmol) in 40 mL of dioxane. The mixturewas stirred at room temperature for 4 hours and left overnight. To themixture were added saturated brine and ethyl acetate, and the two layerswere separated. The aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and evaporated. Theresidue was washed with methanol to give 3.54 g ofN-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-methoxycarbonylbenzamide(Yield: 95.7%) as a light brown solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (9H, s), 3.90 (3H, s), 7.12-7.24(2H, m), 7.55-7.58 (2H, m), 8.09 (2H, d, J=8.8 Hz), 8.10 (2H, d, J=8.8Hz), 8.72 (1H, s), 10.00 (1H, s).

(132-4) A suspension of 3.00 g of the compound from the process (132-3)(8.10 mmol) in 50 mL of methanol and 25 mL of 0.5N lithium hydroxide aq.was heated with stirring at 40° C. for 5 hours. After removing methanolby evaporation, to the residue was added 1N hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was washedwith a small amount of water and saturated brine, dried and evaporated.The residue was washed with methanol to give 2.24 g of terephthalicmono-2-(N-tert-butoxycarbonyl)aminoanilide (Yield: 77.6%) as a lightbrown solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (9H, s), 7.12-7.21 (2H, m),7.53-7.58 (2H, m), 8.06 (2H, d, J=8.8 Hz), 8.10 (2H, d, J=8.8 Hz), 8.71(1H, s), 9.97 (1H, s).

(132-5) To a suspension of 0.20 g of the compound from the process(132-4) (0.56 mmol) in 4 mL of dichloromethane were added 0.14 g ofbenzylamine (1.3 mmol) and then 0.21 mL of triethylamine (1.5 mmol). Tothe solution was added 0.25 g of 2-chloro-1,3-dimethylimidazoliumchloride (1.48 mmol) under ice-cooling, and then the mixture was stirredunder ice-cooling for an hour and at room temperature for an hour. Afterdiluting with chloroform and adding water, the aqueous layer wasextracted with chloroform.

The combined organic layer was washed with saturated brine, dried andevaporated. The residue was purified by column chromatography on silicagel (eluent: chloroform:methanol=10:1). The solid obtained was washedwith diethyl ether to give 279 mg ofN-(2-tert-butoxycarbonylaminophenyl)-4-(N-benzylamino)carbonylbenzamide(Yield: 62.6%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (9H, s), 4.52 (2H, d, J=5.8 Hz),7.13-7.28 (4H, m), 7.34-7.35 (3H, m), 7.56 (2H, d, J=8.1 Hz), 8.05 (4H,s), 8.71 (1H, br.s), 9.23 (1H, t), 9.94 (1H, s).

(132-6) To 151 mg of the compound from the process (132-5) (0.339 mmol)was added 5 mL of 4N hydrochloric acid-dioxane at room temperature, andthe mixture was stirred for 4 hours. After evaporation, the mixture waspartitioned between ethyl acetate and saturated sodium bicarbonate aq.After removing the precipitate, the aqueous layer was extracted withethyl acetate. The combined organic layer was washed with saturatedbrine, dried and evaporated. To the residue was added diethyl ether, andthe precipitate was collected by filtration and dried to give 78 mg ofN-(2-aminophenyl)-4-(N-benzylamino)carbonylbenzamide (Yield: 67%) as awhite solid.

mp: 239-241° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.51 (2H, s),4.93 (2H, br.d), 6.60 (1H, dd, J=7.3, 7.3 Hz), 6.78 (1H, d, J=8.1 Hz),6.95 (1H, dd, J=7.3, 8.3 Hz), 7.18 (1H, d), 7.23-7.35 (5H, m), 8.01 (2H,d, J=8.8 Hz), 8.07 (2H, d, J=8.8 Hz), 9.22 (1H, br.t), 9.81 (1H, br.s).

As described in Example 132, the compound of Example 133 was prepared,whose melting point (mp), ¹H NMR data and IR data are shown below.

Example 133N-(2-Aminophenyl)-4-[N-(2-phenylethyl)amino]carbonylbenzamide (Table 1:Compound 9)

mp: 237-240° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.87 (2H, t,J=7.3 Hz), 3.51 (2H, dt, J=5.9, 7.3 Hz), 4.94 (2H, br.s), 6.60 (1H, dd,J=7.3, 7.3 Hz), 6.78 (1H, d, J=7.3 Hz), 6.98 (1H, dd, J=7.3, 7.3 Hz),7.15-7.34 (6H, m), 7.93 (2H, d, J=8.1 Hz), 8.04 (2H, d, J=8.1 Hz), 8.73(1H, t, J=5.1 Hz), 9.76 (1H, br.s); IR (KBr)cm⁻¹: 3396, 3320, 1625,1602, 1539, 1458, 1313, 699.

Example 134 Preparation ofN-(2-Aminophenyl)-4-[N-(4-nitrophenoxyacetyl)amino]benzamide (Table 1:Compound 54)

(134-1) To a solution of 3 g of the compound from Example 100, theprocess (100-2) (9.2 mmol) and 2.16 g of 4-nitrophenoxyacetic acid (11.0mmol) in 7 mL of DMF were added 2.82 g of dicyclohexylcarbodiimide (13.8mmol) in 5 mL of DMF and a catalytic amount ofN,N-dimethylaminopyridine, and the mixture was stirred for one day.After completion of the reaction, ethyl acetate was added to themixture, insolubles were filtered off through celite, and the solventwas removed by evaporation.

The residue was recrystallized from chloroform to give 2.34 g ofN-[2-(tert-butoxycarbonylamino)phenyl]-4-[(4-nitrophenoxyacetyl)amino]benzamide(Yield: 50%).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (9H, s), 4.97 (2H, s), 7.12-7.26(3H, m), 7.23 (2H, d, J=8.8 Hz), 7.53 (1H, dt, J=2.2, 7.3 Hz), 7.79 (2H,d, J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 8.25 (2H, d, J=8.8 Hz), 8.71 (1H,s), 9.79 (1H, s), 10.52 (1H, s).

(134-2) To a solution of 0.7 g of the compound from the process (134-1)(1.38 mmol) in 10 mL of acetonitrile was added 1.26 mL ofiodotrimethylsilane (8.85 mmol) at room temperature, and the solutionwas stirred for 2 hours. After completion of the reaction, the solutionwas concentrated. Ethyl acetate was added to the residue, the solutionwas stirred for 20 min, and the precipitated crystals were collected byfiltration. The crystals were dissolved in methyl ethyl ketone. Thesolution was washed with saturated sodium thiosulfate aq. and saturatedbrine in sequence, dried over anhydrous magnesium sulfate, andevaporated. The residue was washed with ethyl acetate to give 0.22 g ofN-(2-aminophenyl)-4-[N-(4-nitrophenoxyacetyl)amino]benzamide (Yield:39%) as white crystals.

mp: 212-215° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.97 (2H, s),6.88 (1H, t, J=7.3 Hz), 6.99 (1H, d, J=7.3 Hz), 7.11 (1H, t, J=7.3 Hz),7.23 (2H, d, J=8.8 Hz), 7.24 (1H, m), 7.77 (2H, d, J=8.8 Hz), 8.00 (2H,d, J=8.8 Hz), 8.25 (2H, d, J=8.8 Hz), 9.89 (1H, s), 10.52 (1H, s); IR(KBr)cm⁻¹: 3382, 3109, 1650, 1591, 1508, 1341.

Example 135 Preparation ofN-(2-Aminophenyl)-4-[(4-aminophenoxyacetyl)amino]benzamide (Table 1:Compound 55)

To a solution of 1.41 g of the compound from Example 134, the process(134-1) (2.78 mmol) in 15 mL of methanol and 25 mL of THF was added 10%Pd—C, and the mixture was stirred in an atmosphere of hydrogen, at roomtemperature for an hour. After completion of the reaction, the catalystwas filtered off and the filtrate was concentrated. The residue wastriturated with diisopropyl ether to give 1.1 g ofN-[2-(tert-butoxycarbonylamino)phenyl]-4-[(4-aminophenoxyacetyl)amino]benzamide.

The product was dissolved in 15 mL of acetonitrile. To the solution wasadded 0.74 mL of iodotrimethylsilane (5.20 mmol), and the mixture wasstirred at room temperature for 3 hours. After completion of thereaction, the mixture was evaporated. The residue was washed with methylethyl ketone to give 0.86 g ofN-(2-aminophenyl)-4-[(4-aminophenoxyacetyl)amino]benzamide (Yield: 83%)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.82 (2H, s), 7.13(2H, d, J=8.8 Hz), 7.30-7.48 (6H, m), 7.82 (2H, d, J=8.8 Hz), 8.03 (2H,d, J=8.8 Hz), 10.34 (1H, s), 10.46 (1H, s); IR (KBr)cm⁻¹: 2873, 2590,1680, 1602, 1505, 1243.

Example 136 Preparation ofN-(2-Aminophenyl)-4-(5-phenoxymethyl-1,3-oxazolin-2-on-3-yl)benzamide(Table 2: Compound 1)

(136-1) To 0.7 g of tert-butyl 4-(N-benzyloxycarbonylamino)benzoate(2.14 mmol) in 10 mL of THF at −78° C. was added dropwise 1.33 mL ofn-butyl lithium (2.25 mmol) over 5 min. The mixture was stirred at thesame temperature for 1.5 hours. To the mixture was then added 0.31 mL ofphenylglycidol (2.29 mmol), and the reaction mixture was then stirred atthe same temperature for an hour and left overnight at room temperature.After adding saturated ammonium chloride aq., the mixture was extractedtwice with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and evaporated. The residue was recrystallized fromdiethyl ether to give 0.31 g ofN-[4-(tert-butoxycarbonyl)phenyl]-5-phenoxymethyl-1,3-oxazolin-2-one(Yield: 39%).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.53 (9H, s), 3.97 (1H, dd, J=6.0, 8.8Hz), 4.23-4.34 (3H, m), 5.11 (1H, m), 6.94-7.00 (3H, m), 7.31 (2H, m),7.71 (2H, d, J=8.8 Hz), 7.93 (2H, d, J=8.8 Hz).

(136-2) To a solution of 0.26 g of the compound from the process (136-1)(0.704 mmol) in 4 mL of acetonitrile was added 0.15 mL of trimethylsilyliodide (1.05 mmol), and the solution was stirred at room temperature for2 hours. After completion of the reaction, the solution wasconcentrated. The concentrate was triturated with ethyl acetate-methylethyl ketone to give 0.2 g ofN-(4-carboxyphenyl)-5-phenoxymethyl-1,3-oxazolin-2-one (Yield: 91%).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.98 (1H, dd, J=6.6, 9.6 Hz), 4.23-4.34(3H, m), 5.10 (1H, m), 6.94-6.99 (3H, m), 7.30 (2H, t, J=8.1 Hz), 7.72(2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz), 12.85 (1H, s).

(136-3) To a solution of 0.15 g of the compound from the process (136-2)(0.479 mmol) in 7 mL of dichloromethane were added a catalytic amount ofDMF and 0.12 mL of oxalyl chloride (1.40 mmol), and the solution wasstirred at room temperature for 2 hours. The solution was concentratedand the residual solvent was azeotropically removed twice with toluene.To a solution of the residue in 4 mL of dichloromethane were added asolution of 0.105 g of the compound from Example 1, the process (1-2)(0.504 mmol) and 0.12 g of pyridine (1.52 mmol) in 1 mL ofdichloromethane under ice-cooling, and the solution was warmed to roomtemperature and stirred for an hour. After completion of the reaction,water was added. The mixture was extracted twice with chloroform. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated. The residue was triturated withdiisopropyl ether to give 0.25 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-(5-phenoxymethyl-1,3-oxazolin-2-on-3-yl)benzamide(Yield: quantitative).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.52 (9H, s), 4.11 (1H, dd, J=5.9, 6.6Hz), 4.21-4.27 (3H, m), 5.01 (1H, m), 6.84 (1H, br.s), 6.91 (2H, d,J=8.8 Hz), 7.01 (1H, t, J=7.4 Hz), 7.12-7.34 (5H, m), 7.68 (2H, d, J=8.8Hz).

(136-4) To a solution of 0.22 g of the compound from the process (136-3)(0.437 mmol) in 4 mL of acetonitrile was added 0.1 mL of trimethylsilyliodide (0.703 mmol) at room temperature, and the solution was stirredfor 2 hours. After adding saturated sodium thiosulfate aq., the mixturewas extracted twice with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate and evaporated. The residue wasrecrystallized from methanol to give 0.13 g ofN-(2-aminophenyl)-4-(5-phenoxymethyl-1,3-oxazolin-2-on-3y)benzamide(Yield: 74%) as white crystals.

mp: 165-170° C. (dec.); ¹H NMR (270MHz, DMSO-d₆) δ ppm: 4.01 (1H, dd,J=6.6, 9.6 Hz), 4.28-4.34 (3H, m), 5.12 (1H, m), 5.23 (2H, br.s), 6.64(1H, t, J=7.4 Hz), 6.81 (1H, d, J=8.1 Hz), 6.95-7.00 (3H, m), 7.18 (1H,d, J=6.6 Hz), 7.31 (2H, t, J=8.1 Hz), 7.72 (2H, d, J=8.8 Hz), 8.05 (2H,d, J=8.8 Hz), 9.69 (1H, s); IR (KBr)cm⁻¹: 3393, 1740, 1610, 1508, 1253.

As described in Example 136, the compounds of Examples 137 to 143 wereprepared, each of whose melting point (mp), ¹H NMR data and/or IR dataare shown below.

Example 137N-(2-Aminophenyl)-4-[5-(4-nitrophenoxy)methyl-1,3-oxazolin-2-on-3-yl-yl]benzamide(Table 2: Compound 2)

mp: 162-164° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.97 (1H, dd, J=6.6,9.5 Hz), 4.10 (1H, dd, J=5.1, 11.0 Hz), 4.17 (1H, dd, J=3.7, 11.0 Hz),4.27 (1H, t, J=8.8 Hz), 6.53-6.80 (6H, m), 6.97 (1H, t, J=8.1 Hz), 7.16(1H, d, J=6.6 Hz), 7.72 (2H, d, J=8.8 Hz), 8.04 (2H, d, J=8.8 Hz), 9.65(1H, s); IR (KBr)cm⁻¹: 3356, 2365, 1741, 1609, 1510, 1247.

Example 138N-(2-Aminophenyl)-4-(5-benzyloxymethyl-1,3-oxazolin-2-on-3-yl)benzamideHydrochloride (Table 2: Hydrochloride of Compound 3)

mp: 181-183° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.69 (1H, dd, J=5.2,11.0 Hz), 3.76 (1H, dd, J=3.7, 11.0 Hz), 3.91 (1H, dd, J=5.9, 8.8 Hz),4.59 (2H, s), 4.93 (1H, m), 7.26-7.41 (8H, m), 7.51 (1H, m) 7.74 (2H, d,J=8.8 Hz), 8.15 (2H, d, J=8.8 Hz, 10.42 (1H, s).

Example 139N-(2-Aminophenyl)-4-[5-(pyridin-3-yl)oxymethyl-1,3-oxazolin-2-on-3-yl]benzamide(Table 2: Compound 4)

mp: 199-201° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.01 (1H, dd, J=6.6,8.8 Hz), 4.28-4.46 (3H, m), 4.96 (2H, br.s), 5.14 (1H, m), 6.61 (1H, t,J=7.4 Hz), 6.79 (1H, d, J=7.4 Hz), 6.98 (1H, t, J=7.4 Hz), 7.16 (1H, d,J=7.4 Hz), 7.36 (1H, dd, J=4.4, 8.1 Hz), 7.44 (1H, dd, J=1.5, 8.1 Hz);IR (KBr)cm⁻¹: 2815, 2631, 2365, 1752, 1610, 1520, 1225.

Example 140N-(2-Aminophenyl)-4-[5-(pyridin-3-yl)methyloxymethyl-1,3-oxazolin-2-on-3-yl]benzamide(Table 2: Compound 5)

mp: 160-164° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.73 (1H, dd,J=5.2, 11.7 Hz), 3.79 (1H, dd, J=2.9, 11.7 Hz), 3.91 (1H, dd, J=5.9, 8.8Hz), 4.21 (1H, t, J=8.8 Hz), 4.62 (2H, s), 4.91 (3H, br.s), 6.60 (1H, t,J=7.4 Hz), 6.78 (1H, d, J=7.4 Hz), 6.98 (1H, t, J=7.4 Hz), 7.16 (1H, d,J=7.4 Hz), 7.38 (1H, dd, J=4.4, 7.4 Hz), 7.69 (2H, d, J=8.8 Hz), 7.71(1H, m), 8.03 (2H, d, J=8.8 Hz), 8.51 (1H, dd, J=1.5, 4.4 Hz), 8.54 (1H,d, J=1.5 Hz), 9.65 (1H, s); IR (KBr)cm⁻¹: 3368, 1742, 1648, 1608, 1492,1226.

Example 141N-(2-Aminophenyl)-4-[5-(3-nitrophenoxy)methyl-1,3-oxazolin-2-on-3-yl]benzamide(Table 2: Compound 6)

mp: 230° C. (dec.); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.04 (1H, t, J=8.8Hz), 4.32 (1H, t, J=8.8 Hz), 4.41-4.53 (2H, m), 4.91 (2H, s), 5.15 (1H,m), 6.61 (1H, t, J=7.4 Hz), 6.79 (1H, d, J=7.4 Hz), 6.98 (1H, t, J=7.4Hz), 7.16 (1H, d, J=7.4 Hz), 7.46 (1H, dd, J=1.5, 8.1 Hz), 7.61 (1H, t,J=8.1 Hz), 7.71-7.79 (3H, m), 7.87 (1H, d, J=8.1 Hz), 8.06 (2H, d, J=8.8Hz), 9.66 (1H, s); IR (KBr)cm⁻¹: 3363, 3095, 2365, 1741, 1608, 1529.

Example 142N-(2-Aminophenyl)-4-[5-(pyridin-2-yl)methyloxymethyl-1,3-oxazolin-2-on-3-yl]benzamide(Table 2: Compound 7)

mp: 172-174° C.;

¹H NMR (270MHz, DMSO-d₆) δ ppm: 3.79 (1H, dd, J=5.2, 11.0 Hz), 3.85 (1H,dd, J=2.9, 11.0 Hz), 3.95 (1H, dd, J=6.6, 9.6 Hz), 4.23 (1H, t, J=9.6Hz), 4.67 (2H, s), 4.90 (2H, s), 4.95 (1H, m), 6.60 (1H, t, J=7.4 Hz),6.78 (1H, d, J=7.4 Hz), 6.97 (1H, t, J=7.4 Hz), 7.16 (1H, d, J=7.4 Hz),7.29 (1H, dd, J=5.2, 6.6 Hz), 7.40 (1H, d, J=6.6 Hz), 7.70 (2H, d, J=8.8Hz), 7.78 (1H, dt, J=2.2, 7.4 Hz), 8.03 (2H, d, J=8.8 Hz), 8.51 (1H, d,J=4.4 Hz), 9.64 (1H, s); IR (KBr)cm⁻¹: 3369, 1743, 1651, 1608, 1492,1283.

Example 143N-(2-Aminophenyl)-4-[5-(pyridin-2-yl)oxymethyl-1,3-oxazolin-2-on-3-yl]benzamide(Table 2: Compound 8)

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.96 (1H, dd, J=5.9,9.6 Hz), 4.21-4.40 (3H, m), 4.90 (2H, s), 5.03 (1H, m), 6.28 (1H, t,J=6.6 Hz), 6.43 (1H, d, J=99.6 Hz), 6.60 (1H, t, J=6.6 Hz), 6.78 (1H, d,J=6.6 Hz), 6.97 (1H, t, J=7.4 Hz), 7.15 (1H, d, J=6.6 Hz), 7.46 (1H, dt,J=7.4, 1.5 Hz), 7.67 (2H, d, J=8.8 Hz), 7.69 (1H, m), 8.03 (2H, d, J=8.8Hz), 9.64 (1H, s).

Example 144N-(2-Aminophenyl)-4-[N-[3-[(pyridin-3-yl)methylamino]cyclobuten-1,2-dion-4-yl]aminomethyl]benzamide(Table 2: Compound 9)

(144-1) To a solution of 0.073 g of3,4-di-n-butoxy-3-cyclobuten-1,2-dione (0.323 mmol) in 2 mL of THF wasadded 0.1 g of the compound from Example 1, the process (1-4) (0.293mmol), and the solution was stirred for 4 hours. After adding 0.033 mLof 3-aminomethylpyridine (0.327 mmol), the solution was reacted for aday. After completion of the reaction, water was added to the solution,and the mixture was extracted twice with methyl ethyl ketone. Theorganic layer was dried over anhydrous magnesium sulfate and evaporated.The residue was triturated with methanol to give 0.12 g ofN-[2-(N-tert-butoxycarbonylamino)phenyl]-4-[N-[3-[(pyridin-3-yl)methylamino]cyclobuten-1,2-dion-4-yl]aminomethyl]benzamide(Yield: 78%).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (9H, s), 4.75-4.81 (4H, m), 7.15(1H, dt, J=2.2, 7.4 Hz), 7.20 (1H, dt, J=2.2, 7.4 Hz), 7.74 (1H, dd,J=2.2, 7.4 Hz), 7.47 (2H, d, J=8.1 Hz), 7.54 (2H, dd, J=2.2, 7.4 Hz),7.73 (1H, m), 7.94 (2H, d, J=8.1 Hz), 8.50 (1H, m), 8.55 (1H, d, J=1.5Hz), 8.67 (1H, s), 9.82 (1H, s).

(144-2) To a solution of 0.1 g of the compound from the process (144-1)(0.19 mmol) in 4 mL of dioxane and 1 mL of methanol was added 4 mL of 4Nhydrochloric acid-dioxane, and the mixture was reacted for 2 hours.After completion of the reaction, the mixture was concentrated andneutralized with saturated sodium bicarbonate aq. Methyl ethyl ketonewas added to the mixture, and the precipitated crystals were collectedby filtration to give 0.04 g ofN-(2-aminophenyl)-4-[N-[3-[(pyridin-3-yl)methylamino]cyclobuten-1,2-dion-4-yl]aminomethyl]benzamide(Yield: 49%).

mp: 230° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.76 (2H, s), 4.79 (2H,s), 4.90 (2H, s), 6.60 (1H, t, J=7.4 Hz), 6.78 (1H, d, J=7.4 Hz), 6.97(1H, t, J=7.4 Hz), 7.16 (1H, d, J=7.4 Hz), 7.39 (1H, m), 7.43 (2H, d,J=8.1 Hz), 7.73 (1H, d, J=8.1 Hz), 7.97 (2H, d, J=8.1 Hz), 7.99 (1H,br.s), 8.51 (1H, d, J=8.1 Hz), 8.55 (1H, s), 9.64 (1H, s).

Example 145N-(2-Aminophenyl)-4-[3-(pyridin-3-yl)methylimidazolin-2-on-1-yl]methylbenzamide(Table 2: Compound 10)

(145-1) Potassium carbonate (7.88 g; 57 mmol) was added to a solution of4.92 g of ethylene urea (57 mmol), 5.73 g of methyl4-bromomethylbenzoate (25 mmol) and 1.85 g of tetra-n-butylammoniumiodide (5.0 mmol) in 30 mL of DMF, and the mixture was heated withstirring at 80° C. for 5 hours. After cooling, the solid was collectedby filtration and washed with ethyl acetate. The filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (eluent: ethyl acetate:methanol=10:1). To the light yellowoil obtained was added diisopropyl ether, and the precipitated solid wascollected by filtration and dried to give 3.36 g ofN-(4-methoxycarbonylphenylmethyl)imidazolin-2-one (Yield: 57.4%) as alight brown solid.

¹H NMR (270 MHz, CDCl₃) δ ppm: 3.28-3.35 (2H, m), 3.41-3.47 (2H, m),3.92 (3H, s), 4.42 (2H, s), 4.61 (1H, br.s), 7.35 (2H, d, J=8.1 Hz),8.01 (2H, d, J=8.1 Hz).

(145-2) Saturated sodium bicarbonate aq. was added to 2.05 g of3-chloromethylpyridine hydrochloride (12.5 mmol), and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried and evaporated. The residual solvent wasazeotropically removed from the residue with toluene. To the residue wasadded 5 mL of DMF and then 0.37 g of tetra-n-butylammonium iodide (1.0mmol) to prepare a solution of a benzyl halide in DMF. To a suspensionof 0.30 g of sodium hydride (60% oil dispersion) (7.5 mmol) in 5 mL ofDMF was slowly added dropwise a solution of 1.17 g of the compound fromthe process (145-1) (5.0 mmol) in 10 mL of DMF, and the solution wasstirred at room temperature for 30 min. After adding the above solutionof the benzyl halide, the resulting solution was heated with stirring at80° C. for 7 hours, and then left at room temperature overnight. Afterremoving DMF, the residue was partitioned between ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate-methyl ethylketone (2:1). The combined organic layer was washed with saturatedbrine, dried and evaporated. The residue was purified by columnchromatography on silica gel (eluent: ethyl acetate:methanol=10:1) togive 1.17 g ofN-(4-methoxycarbonylphenylmethyl)-N′-(pyridin-3-yl)methylimidazolin-2-one(Yield: 72.3%) as a brown oil.

¹H NMR (270MHz, CDCl₃) δ ppm: 3.20 (4H, s), 3.92 (3H, s), 4.44 (2H, s),4.46 (2H, s), 7.27-7.36 (3H, m), 7.64-7.69 (1H, m), 8.01 (2H, d, J=8.1Hz), 8.53-8.56 (2H, m).

(145-3) To a solution of 0.55 g of the compound from the process (145-2)(1.7 mmol) in 8 mL of methanol and 8 mL of water were added 110 mg oflithium hydroxide monohydrate (1.7 mmol) at room temperature, and thesolution was heated with stirring at 50° C. for 1.5 hours. Additionallithium hydroxide monohydrate (0.05 g; 1.2 mmol) was added, and thesolution was stirred at −50° C. for additional 1.5 hours. The solutionwas acidified to pH 3-4) with 10% hydrochloric acid. Saturated brine wasadded, and the mixture was extracted twice with ethyl acetate and oncewith ethyl acetate-methyl ethyl ketone (1:1). The organic layer wasdried over anhydrous sodium sulfate and evaporated. The residue wasdried to give 0.32 g of4-[3-(pyridin-3-yl)methylimidazolin-2-on-1-yl]methylbenzoic acid (Yield:61%) as a brown oil.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.17 (2H, s), 3.20 (2H, s), 4.36 (2H,s), 4.38 (2H, s), 7.35-7.42 (3H, m), 7.68 (1H, dd, J=6.6 Hz), 7.92 (2H,d, J=8.1 Hz), 8.51 (2H, m).

(145-4) To a solution of 0.31 g of the compound from the process (145-3)(1.0 mmol) in 12 mL of dichloromethane was added dropwise 0.3 mL ofoxalyl chloride (3.5 mmol) at room temperature, and the solution wasstirred at room temperature for 30 min and then at 40° C. for 1.5 hours.After evaporation, the residual solvent was azeotropically removed withtoluene, and the residue was suspended in 10 mL of dichloromethane. Tothe suspension under ice-cooling was added dropwise 0.21 g of thecompound from Example 1, the process (1-2) (1.0 mmol) in 2 mL ofdichloromethane and 2 mL of pyridine. The mixture was warmed withstirring to room temperature and left at room temperature overnight.After adding saturated sodium bicarbonate aq., the mixture was extractedwith chloroform. The organic layer was washed with saturated brine,dried and evaporated. The residue was purified by column chromatographyon silica gel (eluent: ethyl acetate:methanol=20:1) to give 0.10 g ofN-(2-tert-butoxycarbonylaminophenyl)-4-[3-(pyridin-3-ylmethyl)imidazolin-2-on-1-yl]methylbenzamide(Yield: 20%) as a brown oil.

¹H NMR (270 MHz, CDCl₃) δ ppm: 1.52 (9H, s), 3.20 (4H, s), 4.45 (2H, s),4.48 (2H, s), 6.75 (1H, br.s), 7.15-7.40 (5H, m), 7.65-7.70 (2H, m),7.83 (1H, d, J=7.3 Hz), 7.94 (2H, d, J=8.1 Hz), 8.50-8.60 (3H, br.m).

(145-5) To a solution of 100 mg of the compound from the process (145-4)(0.20 mmol) in 2 mL of dioxane was added 2 mL of 4N hydrochloricacid-dioxane and then 0.5 mL of methanol to make the mixture homogenous.After stirring for 2 hours, the solution was neutralized with saturatedsodium bicarbonate and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried and evaporated. The residue wasdried under reduced pressure to give 47 mg ofN-(2-aminophenyl)-4-[3-(pyridin-3-yl)methylimixazolin-2-on-1-yl]methylbenzamide(Yield: 58%) as a brown oil.

mp: (amorphous); ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 3.20 (4H, s), 4.37(2H, s), 4.39 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J=7.3, 7.3 Hz),6.78 (1H, d, J=8.1 Hz), 6.97 (1H, dd, J=6.6, 7.3 Hz), 7.16 (1H, d, J=7.3Hz), 7.35-7.41 (3H, m), 7.68 (1H, d, J=8.1 Hz), 7.90-8.00 (2H, m), 8.50(2H, br.s), 9.63 (1H, br.s).

Example 146 Preparation ofN-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide0.5 Fumarate (Table 1: Fumarate of Compound 82)

To 10 mL of methanol were added 310 mg of the compound from Example 48,and the mixture was heated to dissolve the solid. To the solution wasadded 96 mg of fumaric acid in methanol, and the solution was cooled.The precipitated crystals were collected by filtration andrecrystallized from 5 mL of methanol to give 200 mg of the desiredproduct (Yield: 56%).

mp:. 166-167° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=6.6Hz), 5.10 (2H, s), 6.60 (1H, t, J=8.0 Hz), 6.63 (1H, s), 6.78 (1H, d,J=8.0 Hz), 6.90-7.50 (5H, m), 7.70-8.00 (4H, m), 8.53 (1H, d, J=3.6 Hz),8.60 (1H, s), 9.63 (1H, s); IR (KBr)cm⁻¹: 3332, 1715, 1665, 1505, 1283,1136, 1044, 983, 760, 712; Elementary analysis for C₂₁H₂₀N₄O₃+1/2C₄H₄O₄.

C H N Calculated: 63.59 5.10 12.90 Observed: 63.56 5.22 12.97

As described in Example 146, the compounds of Examples 147 to 149 areprepared, each of whose melting point (mp), ¹H NMR data, IR data and/orelementary analysis data are shown below.

Example 147N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamideMaleate (Table 1: Maleate of Compound 82)

mp: 123-124° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.28 (2H, d, J=6.6Hz), 5.11 (2H, s), 6.24 (2H, s), 6.66 (1H, t, J=8.0 Hz), 6.83 (1H, d,J=8.0 Hz), 6.90-8.00 (9H, m), 8.56 (1H, d, J=3.6 Hz), 8.62 (1H, s), 9.69(1H, s); IR (KBr)cm⁻¹: 3298, 1719, 1546, 1365, 1313, 1250, 1194, 1149,1044, 993, 862, 751; Elementary analysis for C₂₁H₂₀N₄O₃+C₄H₄O₄+0.3H₂O.

C H N Calculated: 60.31 4.98 11.25 Observed: 60.52 5.12 11.03

Example 148N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamideHydrochloride (Table 1: Hydrochloride of Compound 82)

mp: 140 (dec.) ° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.31 (2H, d, J=5.8Hz), 5.24 (2H, s), 7.10-7.60 (6H, m), 7.90-8.50 (5H, m), 8.70-8.90 (2H,m), 10.46 (1H, s); IR (KBr)cm⁻¹: 2553, 1715, 1628, 1556, 1486, 1254,1049, 778, 687.

Example 149N-(2-Aminophenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide 0.7Fumarate (Table 1: Fumarate of Compound 61)

As described in Example 146, the title compound was prepared from thecompound of Example 46.

mp: 154-155° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.42 (2H, d, J=5.9Hz), 4.69 (2H, s), 6.60 (1H, t, J=8.0 Hz), 6.63 (0.7H, s), 6.78 (1H, d,J=8.0 Hz), 6.90-7.50 (6H, m), 7.93 (2H, d, J=8.0 Hz), 8.20-8.40 (2H, m),8.82 (1H, br.s), 9.63 (1H, s); IR (KBr)cm⁻¹: 3324, 1709, 1631, 1521,1457 ,1428, 1260, 1064, 806, 698; Elementary analysis forC₂₁H₂₀N₄O₃+0.7C₄H₄O₄+0.7H₂O.

C H N Calculated: 60.79 5.19 11.91 Observed: 60.95 5.20 11.75

Comparative Example 1N-(3-Aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide

As described in Example 48, the title compound was prepared.

mp: 156° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.27 (2H, d, J=6.6 Hz),5.06 (2H, s), 5.10 (2H, s), 6.20-6.40 (1H, m), 6.80-7.10 (3H, m),7.30-7.50 (3H, m), 7.70-8.00 (4H, m), 8.53 (1H, d, J=3.6 Hz), 8.59 (1H,s), 9.88 (1H, s); IR (KBr)cm⁻¹: 3327, 3218, 1708, 1639, 1536, 1279,1147, 1050, 859, 788.

Comparative Example 2N-(4-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide

As described in Example 48, the title compound was prepared.

mp: 204-205° C.; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 4.27 (2H, d, J=6.6Hz), 4.91 (2H, s), 5.10 (2H, s), 6.52 (2H, d, J=8.8 Hz), 7.30-7.50 (5H,m), 7.70-8.00 (4H, m), 8.50-8.60 (2H, m), 9.80 (1H, s); IR (KBr)cm⁻¹:3336, 3224, 1706, 1638, 1530, 1279, 1145, 1050, 1005, 827.

Pharmacological Test Example 1

Test for Induction of Differentiation in A2780 Cells

Increase of alkaline phosphatase (ALP) activity is known as an indicatorfor differentiation of human colon cancer cells. For example, it isknown that sodium butylate may increase ALP activity (Young et al.,Cancer Res., 45, 2976 (1985); Morita et al., Cancer Res., 42, 4540(1982)). Thus, differentiation inducing action was evaluated using ALPactivity as an indicator.

Experimental Procedure

To each well of a 96-well plate was placed 0.1 mL of A2780 cells (15,000cells/well) and the next day was added 0.1 mL of a sequential dilute oftest solution with the medium. After incubation for 3 days, the cells onthe plate were washed twice with a TBS buffer (20 mM Tris, 137 mM NaCl,pH 7.6). Then, to each well was added 0.05 mL of 0.6 mg/mLp-nitrophenylphosphate (9.6% diethanolamine, 0.5 mM MgCl₂ (pH 9.6))solution; and the plate was incubated at room temperature for 30 min.The reaction was quenched with 0.05 mL/well of 3N sodium hydroxide aq.For each well, an absorbance at 405 nm was measured to determine theminimum concentration of the drug inducing increase of ALP activity(ALPmin).

Results

The results are shown in Table 5.

TABLE 5 Differentiation-inducing action to A2780 cells Test CompoundALPmin (μM) Example 1 1 Example 2 3 Example 3 3 Example 4 1 Example 5 1Example 6 1 Example 7 1 Example 8 1 Example 9 1 Example 10 3 Example 111 Example 13 1 Example 15 3 Example 16 3 Example 17 3 Example 18 3Example 23 1 Example 24 1 Example 25 3 Example 26 1 Example 27 10Example 28 10 Example 29 10 Example 30 0.1 Example 31 10 Example 32 3Example 33 0.3 Example 34 0.1 Example 35 0.3 Example 36 10 Example 37 1Example 38 3 Example 39 0.1 Example 40 10 Example 41 0.3 Example 42 10Example 43 3 Example 44 0.01 Example 45 0.003 Example 46 0.1 Example 480.1 Example 49 1 Example 50 1 Example 51 1 Example 52 1 Example 53 3Example 54 1 Example 55 1 Example 56 3 Example 57 3 Example 58 3 Example59 3 Example 60 3 Example 63 3 Example 64 3 Example 65 3 Example 66 3Example 67 3 Example 68 3 Example 70 0.1 Example 71 10 Example 72 10Example 73 3 Example 74 10 Example 76 1 Example 77 3 Example 79 0.1Example 80 0.1 Example 81 10 Example 82 1 Example 85 3 Example 86 0.3Example 87 0.1 Example 88 0.1 Example 89 0.3 Example 90 3 Example 91 0.1Example 92 3 Example 93 3 Example 94 3 Example 95 3 Example 96 10Example 97 0.1 Example 98 0.1 Example 99 3 Example 100 1 Example 3 101Example 3 102 Example 1 103 Example 1 104 Example 1 105 Example 1 106Example 1 107 Example 3 108 Example 1 109 Example 3 110 Example 3 111Example 0.1 112 Example 0.3 113 Example 3 114 Example 0.01 115 Example0.01 116 Example 3 119 Example 0.3 120 Example 3 121 Example 0.03 122Example 3 123 Example 3 124 Example 0.1 125 Example 3 126 Example 0.3127 Example 0.1 128 Example 1 129 Example 0.03 130 Example 0.3 131Example 10 132 Example 3 133 Example 3 134 Example 3 135 Example 1 136Example 1 137 Example 1 138 Example 0.3 139 Example 0.3 140 Example 1141 Example 0.1 142 Example 3 143 Example 3 145 Comp. Ex. 1 >100 Comp.Ex. 2 >100

Pharmacological Test Example 2

Antitumor Test Procedure

Murine myeloid leukemia cells WEHI-3 (1 to 3×10⁶ cells) wereintraperitoneally inoculated to a Balb/C mouse, and administration of atest compound was initiated on the next day. The day was Day 1 andsubsequently the drug was orally administered once a day in Day 1 to 4and in Day 7 to 11. Survival days after inoculation were observed, whichwere used to calculate the ratio of the survival days for the testcompound group to those for the control group (T/C, %). The ratio wasused to evaluate a life prolongation effect.

Results

The results are shown in Table 6.

TABLE 6 Antitumor action to WEHI-3 cells Test Dose (μmol/ compound kg)T/C (%) Example 45 16 138 Example 46 32 141 Example 48 130 190 Example130 189 130

Pharmacological Test Example 3

Antitumor Action Test

Experimental Procedure

To a nude mouse was inoculated tumor cells subcutaneously subcultured ina nude mouse (HT-29, KB-3-1). When the volume became about 20 to 100 mm³and take was confirmed, administration of a drug was initiated. This daywas Day 1, and subsequently the drug was orally administered in Day 1 to5, in Day 8 to 12, Day 15 to 19 and in Day 22 to 26.

The volume of the tumor was determined from the following equation:

(Volume of a tumor)=½×(major axis)×(minor axis)²

Results

The results for the compound of Example 48 (dose: 66 μmol/kg) againstHT-29 are shown in FIG. 1.

The results for the compound of Example 48 (dose: 66 μmol/kg) againstKB-3-1 are shown in FIG. 2.

Calculation Example

Model Construction of Superposition Using High Activity Compounds

Three dimensional structure was superimposed using the compounds ofExamples 45, 46 and 48 which exhibit a high differentiation-inducingactivity, to extract information on spatial configurations of atomicgroups necessary for expression of their activity.

For this purpose, any of commercially available program packages, e.g.,CATALYST(MSI), Cerius2/QSAR+(MSI) and SYBYL/DISCO(Tripos), may be usedto perform a similar level of analysis. Here, SYBYL/DISCO(Tripos) wasused for construction of a superimposed structure and analyses.

For the compound of Example 48, a three-dimensional structure wasgenerated using the sketch function of SYBYL, a point charge wasallocated on each atom by Gasteiger-Huckel method, and the structure wasoptimized using Tripos force field. A dummy atom was placed at sitespossibly interacting with a biomolecule in order to determine the siteswhere such an interaction may occur and which may be important for aninteraction between a drug and a biomolecule, e.g., ahydrophobic-interaction site (e.g., an aromatic ring and an aliphaticside chain) and a hydrogen-bonding site (e.g., a carbonyl oxygen,hydroxyl and amino). The interactions were categorized in order toidentify the types of interaction, e.g., hydrophobic interaction,hydrogen bond and electrostatic interaction, and a different type ofdummy atom was allocated to each of the interactions. Furthermore,conformers were generated by rotating the molecule at a rotatable bondto retain a conformation in which there was a change of the distancebetween dummy atoms allocated at the possible interaction sites, in aconformation file as a candidate conformation. For the compounds ofExamples 45 and 46, three dimensional structures were constructed andconformations were generated as described for the compound of Example48.

Using the compound of Example 48 as a template, for each of itsconformations a superimposed structure was constructed so that the dummyatoms showing the same type of interaction were superimposed for bothconformations of Examples 45 and 46.

For the superimposed structures, the optimal superimposed structure wasselected according to the analysis results of the three dimensional QSARusing the number of the dummy atoms used in the superimposition (thenumber of common interactions), the degree of steric superimposition(volume of superimposition) and the activity values.

It was found that in the superimposed structure obtained, the centroidof ring B (W1), the centroid of ring A (W2) and hydrogen bond acceptor(e.g., carbonyl oxygen)(W3) in formula (13) are positioned in a mannerthat there are the following relationships between them; W1-W2=8.34 Å,W1-W3=3.80 Å and W2-W3=5.55 Å.

Calculation Example 1: the Compound of Example 130

Appropriate 7 atoms were selected from the possible interaction sitesand the constituent atoms of the benzamide structure of the compound ofExample 130, and optimization was performed by applying restrainedpotential to the compound of Example 130, using the compounds ofExamples 45, 46 and 48 used in the above superimposition as targetstructures. Then, optimization was performed without restrainedpotential to obtain an active conformation of the compound of Example130. For this active conformation, the centroid of the benzene ring inthe benzamide (W1), the centroid of the pyridine ring (W2) and thecarbonyl carbon (W3) were determined to extract the parameters on itsspatial configuration.

All conformations were generated for the rotatable bonds, and for eachof the conformations, an energy level was calculated to determine themost stable structure. The energy level of the most stable structure wascalculated to determine the difference from the active conformation. Asa result, it was found that the structure obtained may have aconfiguration in which W1-W2=8.43 Å, W1-W3=3.82 Å and W2-W3=5.88 Å(energy difference from the most stable structure=2.86 kcal/mol).

With analysis using the dummy atoms obtained in the construction of theabove superimposed structure model, the same results were obtained.

Results

The results of the calculation are shown in Table 7.

TABLE 7 Calculation results of the parameters on the spatialconfigurations Compound W1-W2 (Å) W1-W3 (Å) W2-W3 (Å) Example 39 8.203.95 5.49 Example 45 8.54 3.85 5.55 Example 46 7.42 3.97 5.93 Example 478.52 3.88 5.96 Example 48 8.43 3.94 5.51 Example 79 7.09 5.20 5.48Example 80 8.59 4.37 5.51 Example 87 6.80 3.80 3.63 Example 88 8.67 3.506.22 Example 8.29 3.75 6.42 124 Example 8.64 3.76 5.90 128 Example 8.433.82 5.88 130 Example 8.59 4.88 5.47 131 Example 7.59 3.94 7.27 136Example 7.58 3.94 7.27 137 Example 9.07 3.94 7.47 138 Example 7.64 3.947.29 139 Example 9.11 3.94 7.50 140 Example 7.60 3.94 7.28 141 Example9.02 3.94 7.44 142 Example 7.62 3.94 7.29 143 Example 8.48 4.40 5.69 145

What is claimed is:
 1. An anilide compound having the structurerepresented by formula (13):

wherein A is an optionally substituted phenyl group or an optionallysubstituted heterocyclic group selected from the group consisting ofpyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole,isoxazole, isothiazole, imidazole, thiazole, oxazole, tetrahydrofuran,piperidine, piperazine, quinuclidine, quinoline, benzofuran,benzothiophene, indole, furopyridine, thienopyridine andpyrrolopyridine, wherein the substituent(s) for the phenyl group or theheterocyclic group is (are) 1 to 3 substituents selected from a nitrogroup or a cyano group or 1 to 4 substituents selected from the groupconsisting of a halogen atom, a hydroxyl group, an amino group, an alkylgroup having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, anaminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to4 carbons, an acyl group having 1 to 4 carbons, an acylamino grouphaving 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, aperfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy grouphaving 1 to 4 carbons, a carboxyl group, an alkoxycarbonyl group having1 to 4 carbons, a phenyl group and a heterocyclic group; B is anoptionally substituted phenyl group or an optionally substitutedheterocyclic group selected from the group consisting of thiophene,benzofuran and benzothiophene, wherein the substituent(s) for the phenylgroup or the heterocyclic group is (are) 1 to 3 substituents selectedfrom a nitro group or a cyano group or 1 to 4 substituents selected fromthe group consisting of a halogen atom, a hydroxyl group, an aminogroup, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylaminogroup having 1 to 4 carbons, an acyl group having 1 to 4 carbons, anacylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4carbons, a perfluoroalkyl group having 1 to 4 carbons, aperfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group, analkoxycarbonyl group having 1 to 4 carbons, a phenyl group and aheterocyclic group; Y, which links A and B is represented by formula(27): -T1-T2-T3-  (27)  wherein T1 is —O—CH₂—, —CH₂—O—CH₂—, —CH₂—NH—,—CH₂—or —O—; T3 is —NH—CH₂—, —CH₂—, —CO—NH—, —CO— or a direct bond; whenT3 is —NH—CH₂—, —CH₂—, or a direct bond, T2 is a cyclic moiety having—CO— or —CS—, said cyclic moiety consisting of one selected from thegroup consisting of an oxazolidine ring, an imidazolidine ring, apiperazine ring, a pyrrolidine ring or a cyclobutene ring, wherein oneor two of said —CO— or —CS— is formulated by combining O or S with oneor two carbon atoms of the cyclic moiety; or when T3 is —CO—NH— or —CO—,T2 is a cyclic moiety consisting of a pyrrolidine ring; R³ is a hydroxyor amino group; or a pharmaceutically acceptable salt thereof.
 2. Ananilide compound or a pharmaceutically acceptable salt thereof asclaimed in claim 1, wherein A is an optionally substituted heterocycle;R³ is an amino group; and Y is a moiety having —CO— which is cyclic andlinks A and B.
 3. An anilide compound or a pharmaceutically acceptablesalt thereof as claimed in claim 1, wherein B is an optionallysubstituted phenyl.
 4. The anilide compound or a pharmaceuticallyacceptable salt thereof as claimed in claim 1, wherein T2 as the cyclicmoiety having —CO— or —CS— is one of the groups illustrated in formula(5)

and T2 as the pyrrolidine ring is:


5. The anilide compound or a pharmaceutically acceptable salt thereof asclaimed in claim 1, wherein Y is one of the groups illustrated informula (6):


6. An anilide compound having the structure represented by formula (13):

wherein A is an optionally substituted phenyl group or an optionallysubstituted heterocyclic group selected from the group consisting ofpyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole,isoxazole, isothiazole, imidazole, thiazole, oxazole, tetrahydrofuran,piperidine, piperazine, quinuclidine, quinoline, benzofuran,benzothiophene, indole, furopyridine, thienopyridine andpyrrolopyridine, wherein the substituent(s) for the phenyl group or theheterocyclic group is (are) 1 to 3 substituents selected from a nitrogroup or a cyano group or 1 to 4 substituents selected from the groupconsisting of a halogen atom, a hydroxyl group, an amino group, an alkylgroup having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, anaminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to4 carbons, an acyl group having 1 to 4 carbons, an acylamino grouphaving 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, aperfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy grouphaving 1 to 4 carbons, a carboxyl group, an alkoxycarbonyl group having1 to 4 carbons, a phenyl group and a heterocyclic group: B is anoptionally substituted heterocyclic group selected from the groupconsisting of thiophene, benzofuran and benzothiophene, wherein thesubstituent(s) for the heterocyclic group is (are)1 to 3 substituentsselected from a nitro group or a cyano group or 1 to 4 substituentsselected from the group consisting of a halogen atom, a hydroxyl group,an amino group, an alkyl group having 1 to 4 carbons, an alkoxy grouphaving 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, analkylamino group having 1 to 4 carbons, an acyl group having 1 to 4carbons, an acylamino group having 1 to 4 carbons, an alkylthio grouphaving 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, aperfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group, analkoxycarbonyl group having 1 to 4 carbons, a phenyl group and aheterocyclic group; Y, which links A and B, is —X—Q—(CH₂)_(n)— wherein Xis a direct bond or a moiety having a structure selected from those informula (2):

wherein e is an integer of 1 to 4; g and m are independently an integerof 0 to 4; R4 is a hydrogen atom or an optionally substituted alkylgroup having 1 to 4 carbons, or the acyl group represented by formula(3)

wherein R6 is an optionally substituted alkyl group having 1 to 4carbons, a perfluoroalkyl group having 1 to 4 carbons, a phenyl group ora heterocyclic group; R5 is a hydrogen atom or an optionally substitutedalkyl group having 1 to 4 carbons; n is an integer of 0 to 4, providedthat when X is a direct bond, n is not zero; Q is a moiety having astructure selected from those in formula (4):

wherein R7 and R8 are independently a hydrogen atom or an optionallysubstituted alkyl group having 1 to 4 carbons; R3 is a hydroxy or aminogroup.